Inhibitors of EGFR and methods of use thereof

ABSTRACT

The disclosure relates to a compound having Formula (I′): 
                         
and
 
in particular, Compound I-126:
 
                         
which modulates the activity of EGFR, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which EGFR plays a role.

RELATED APPLICATIONS

This application is a U.S. National Phase application, filed under 35U.S.C. § 371, of International Application No. PCT/US2016/040421, filedon Jun. 30, 2016, which claims the benefit of, and priority to, U.S.provisional application No. 62/186,563, filed on Jun. 30, 2015, and62/259,895, filed on Nov. 25, 2015, the entire contents of each of whichare incorporated herein by reference in their entireties.

GOVERNMENT SUPPORT

The work described herein was supported by the National Institutes ofHealth, NIH Grant No. P01 CA154303. The U.S. Government has certainrights to the claimed invention.

BACKGROUND OF THE DISCLOSURE

The epidermal growth factor receptor (EGFR, Erb-B1) belongs to a familyof proteins, involved in the proliferation of normal and malignant cells(Arteaga, C. L., J. Clin. Oncol. 19, 2001, 32-40). Overexpression ofEpidermal Growth Factor Receptor (EGFR) is present in at least 70% ofhuman cancers (Seymour, L. K., Curr. Drug Targets 2, 2001, 117-133) suchas, non-small cell lung carcinomas (NSCLC), breast cancers, gliomas,squamous cell carcinoma of the head and neck, and prostate cancer(Raymond et al., Drugs 60 Suppl. 1, 2000, discussion 41-2; Salomon etal., Crit. Rev. Oneal. Hematol. 19, 1995, 183-232; Voldborg et al., Ann.Oneal. 8, 1997, 1197-1206). The EGFR-TK is therefore widely recognizedas an attractive target for the design and development of compounds thatcan specifically bind and inhibit the tyrosine kinase activity and itssignal transduction pathway in cancer cells, and thus can serve aseither diagnostic or therapeutic agents. For example, the EGFR tyrosinekinase (EGFR-TK) reversible inhibitor, TARCEVA®, is approved by the FDAfor treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFRtargeted molecules have also been approved including LAPATINIB® andIRESSA®.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors(TKIs) are effective clinical therapies for EGFR mutant advancednon-small cell lung cancer (NSCLC) patients (Mok, T. S., et al., N.Engl. J. Med. 361, 2009, 947-57; Paez, J. G., et al., Science. 304,2004, 1497-500; Lynch, T. J., et al., N. Engl. J Med. 350, 2004,2129-39; Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46). Severalrandomized clinical trials have demonstrated that EGFR TKIs are moreeffective, as measured by response rate (RR) and progression freesurvival (PFS), than chemotherapy when used as initial systemictreatment for advanced EGFR mutant NSCLC (Mok, T. S., et al., N. Engl.J. Med. 361, 2009, 947-57; Rosell, R., et al., Lancet Oncol. 13, 2012,239-46; Sequist, L. V. et al., J. Clin. Oncol. 31, 2013, 3327-34; Wu, Y.L., et al., Lancet Oncol. 15, 2014, 213-22; Maemondo, M., et al. N.Engl. J. Med. 362, 2010, 2380-8; Zhou, C., et al., Lancet Oncol. 12,2011, 735-42; Mitsudomi, T., et al., Lancet Oncol. 11, 2010, 121-8).However, the vast majority of patients will develop disease progressionfollowing successful treatment with an EGFR TKI. The most commonmechanism of acquired resistance, detected in 60% of patients, is asecondary mutation in EGFR at position T790 (T790M) (Yu, H. A., et al.,Clin. Cancer Res. 19, 2013, 2240-7). This mutation, leads to an increasein ATP affinity, thus making it more difficult for reversible EGFR TKIsgefitinib and erlotinib to bind the EGFR TKI domain (Yun C. H., et al.,Proc. Natl. Acad. Sci. USA. 105, 2008, 2070-5).

Covalent EGFR inhibitors have emerged as strategies to inhibit EGFRT790M containing cancers. However, in lung cancer patients, afatinib isonly effective in EGFR TKI naive EGFR mutant cancers and has a RR of<10% in patients with NSCLC that have developed resistance to gefitinibor erlotinib (Miller V. A., et al., Lancet Oncol. 13, 2012, 528-38).Afatinib is a potent inhibitor of both mutant and wild type (WT) EGFR.Inhibition of WT EGFR leads to toxicities, including skin rash anddiarrhea, which limits the ability to escalate afatinib doses inpatients to those necessary to inhibit EGFR T790M. Irreversiblepyrimidine EGFR inhibitors, including the tool compound WZ4002 andclinical compounds CO-1686 and AZD9291, overcome many of the limitationsof afatinib (Zhou, W., et al., Nature 462, 2009, 1070-4; Walter, A. O.,et al., Cancer Discov. 3, 2013, 1404-15; Cross, D. A., et al., CancerDiscov. 2014). They are not only more potent on EGFR T790M, but alsoselectively inhibit mutant over WT EGFR and hence should lead toincreased clinical efficacy and less toxicity compared with afatinib(Zhou, W., et al.; Walter, A. O., et al; Cross, D. A., et al.).

However, all current EGFR TKIs target the ATP site, and while thirdgeneration irreversible inhibitors can overcome T790M, they are allrendered impotent by the C797S mutation, which is already arising intreated patients. Cetuximab, an anti-EGFR antibody that blocks receptordimerization is not effective in EGFR-mutant NSCLC, because mutationalactivation of the kinase is effectively “downstream” of receptordimerization. Hence, alternative strategies to inhibit EGFR are needed.At present, suitable compounds with alternative mechanisms of actiontargeting mutant EGFR are not available. Thus, there is a need for noveland potent small molecule EGFR inhibitors with alternative mechanisms ofaction targeting mutant EGFR.

SUMMARY OF THE DISCLOSURE

The present disclosure relates to compounds of Formula (I′), as definedherein, that are capable of modulating EGFR activity. The disclosurefeatures methods of treating or preventing a disease in which EGFR playsa role in a subject in need thereof by administering to the subject atherapeutically effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, as defined herein. The methods of thedisclosure can be used to treat diseases in which EGFR plays a role byinhibiting the kinase activity of EGFR.

A first aspect of the disclosure relates to compounds of Formula (I′):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein R₁, R₂, R₃, R₄, R₅, R_(5′),m, and n are described herein in detail below.

Another aspect of the present disclosure relates to a pharmaceuticalcomposition comprising a compound of Formula (I′), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, and a pharmaceutically acceptable carrier. In another aspect,the pharmaceutical composition further comprises a second agent whereinsaid second agent prevents EGFR dimer formation, and a pharmaceuticallyacceptable carrier.

Another aspect of the present disclosure relates to a method ofinhibiting a kinase. The method comprises administering to a subject inneed thereof an effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In one aspect, the method furthercomprises administering to the subject a second agent wherein saidsecond agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method ofinhibiting epidermal growth factor receptor (EGFR). The method comprisesadministering to a subject in need thereof an effective amount of acompound that binds to an allosteric site in EGFR, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof. In another aspect, the method further comprises administeringto the subject a second agent wherein said second agent prevents EGFRdimer formation.

Another aspect of the present disclosure relates to a method ofinhibiting epidermal growth factor receptor (EGFR). The method comprisesadministering to a subject in need thereof an effective amount of acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In anotheraspect, the method further comprises administering to the subject asecond agent wherein said second agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing a disease. The method comprises administering to a subjectin need thereof an effective amount of a compound that binds to anallosteric site in EGFR, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect,the method further comprises administering to the subject a second agentwherein said second agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing a disease. The method comprises administering to a subjectin need thereof an effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In another aspect, the method furthercomprises administering to the subject a second agent wherein saidsecond agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing a kinase mediated disorder. The method comprisesadministering to a subject in need thereof an effective amount of acompound that binds to an allosteric site in EGFR, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof. In another aspect, the method further comprises administeringto the subject a second agent wherein said second agent prevents EGFRdimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing a kinase mediated disorder. The method comprisesadministering to a subject in need thereof an effective amount of acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In anotheraspect, the method further comprises administering to the subject asecond agent wherein said second agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing a disease, wherein the disease is resistant to an EGFRtargeted therapy, such as a therapy with gefitinib, erlotinib, AZD9291,CO-1686 or WZ4002. The method comprises administering to a subject inneed thereof an effective amount of a compound that binds to anallosteric site in EGFR, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect,the method further comprises administering to the subject a second agentwherein said second agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing a disease, wherein the disease is resistant to an EGFRtargeted therapy, such as a therapy with gefitinib, erlotinib, AZD9291,CO-1686 or WZ4002. The method comprises administering to a subject inneed thereof an effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In another aspect, the method furthercomprises administering to the subject a second agent wherein saidsecond agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer, wherein the cancer cell comprises an activatedEGFR. The method comprises administering to a subject in need thereof aneffective amount of a compound that binds to an allosteric site in EGFR,or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In another aspect, the method furthercomprises administering to the subject a second agent wherein saidsecond agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer, wherein the cancer cell comprises an activatedEGFR. The method comprises administering to a subject in need thereof aneffective amount of a compound of Formula (I′), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof. In another aspect, the method further comprises administeringto the subject a second agent wherein said second agent prevents EGFRdimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer in a subject, wherein the subject is identified asbeing in need of EGFR inhibition for the treatment or prevention ofcancer. The method comprises administering to the subject an effectiveamount of a compound that binds to an allosteric site in EGFR, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In another aspect, the method furthercomprises administering to the subject a second agent wherein saidsecond agent prevents EGFR dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer in a subject, wherein the subject is identified asbeing in need of EGFR inhibition for the treatment or prevention ofcancer. The method comprises administering to the subject an effectiveamount of a compound of Formula (I′), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Inanother aspect, the method further comprises administering to thesubject a second agent wherein said second agent prevents EGFR dimerformation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer, wherein the cancer cell comprises an activatedERBB2. The method comprises administering to a subject in need thereofan effective amount of a compound that binds to an allosteric site inERBB2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In another aspect, the method furthercomprises administering to the subject a second agent wherein saidsecond agent prevents ERBB2 dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer, wherein the cancer cell comprises an activatedERBB2. The method comprises administering to a subject in need thereofan effective amount of a compound of Formula (I′), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof. In another aspect, the method further comprises administeringto the subject a second agent wherein said second agent prevents ERBB2dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer in a subject, wherein the subject is identified asbeing in need of ERBB2 inhibition for the treatment of cancer. Themethod comprises administering to the subject an effective amount of acompound that binds to an allosteric site in ERBB2, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In another aspect, the method furthercomprises administering to the subject a second agent wherein saidsecond agent prevents ERBB2 dimer formation.

Another aspect of the present disclosure relates to a method of treatingor preventing cancer in a subject, wherein the subject is identified asbeing in need of ERBB2 inhibition for the treatment of cancer. Themethod comprises administering to the subject an effective amount of acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In anotheraspect, the method further comprises administering to the subject asecond agent wherein said second agent prevents ERBB2 dimer formation.

Another aspect of the present disclosure relates to a kit comprising acompound capable of inhibiting EGFR activity selected from a compound ofFormula (I′), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof. In another aspect, the kitfurther comprises a second agent wherein said second agent prevents EGFRdimer formation.

Another aspect of the present disclosure relates to a compound thatbinds to an allosteric site in EGFR, or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, foruse in the manufacture of a medicament for treating or preventing adisease in which EGFR plays a role. In another aspect, the presentdisclosure relates to a compound that binds to an allosteric site inEGFR, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, and a second agent wherein saidsecond agent prevents EGFR dimer formation for use in the manufacture ofa medicament for treating or preventing a disease in which EGFR plays arole.

Another aspect of the present disclosure relates to a compound ofFormula (I′), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in the manufactureof a medicament for treating or preventing a disease in which EGFR playsa role. In another aspect, the present disclosure relates to a compoundof Formula (I′), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, and a second agentwherein said second agent prevents EGFR dimer formation for use in themanufacture of a medicament for treating or preventing a disease inwhich EGFR plays a role.

Another aspect of the present disclosure relates to the use of acompound that binds to an allosteric site in EGFR, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, in the treatment or prevention of a disease in which EGFR playsa role. In another aspect, the present disclosure relates to the use ofa compound that binds to an allosteric site in EGFR, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, and a second agent wherein saidsecond agent prevents EGFR dimer formation in the treatment orprevention of a disease in which EGFR plays a role.

Another aspect of the present disclosure relates to the use of acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in thetreatment or prevention of a disease in which EGFR plays a role. Inanother aspect, the present disclosure relates to the use of a compoundof Formula (I′), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, and a second agentwherein said second agent prevents EGFR dimer formation in the treatmentor prevention of a disease in which EGFR plays a role.

In one embodiment, in any of the above aspects, a compound of Formula(I′) is Compound I-126:

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof. In one embodiment, Compound I-126is administered in any of the above methods without a second agent whichprevents EGFR dimer formation. In one embodiment, Compound I-126 is foruse in the manufacture of medicament as described above, without asecond agent which prevents EGFR dimer formation. In one embodiment,Compound I-126 is for use in the treatment or prevention as describedabove, without a second agent which prevents EGFR dimer formation

The present disclosure provides inhibitors of EGFR, such as EGFRcontaining one or more mutations, that are therapeutic agents in thetreatment or prevention of diseases such as cancer and metastasis.

The present disclosure further provides compounds and compositions withan improved efficacy and/or safety profile relative to known EGFRinhibitors. The present disclosure also provides agents with novelmechanisms of action toward EGFR kinases in the treatment of varioustypes of diseases including cancer and metastasis.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the chemical structure of Compound A1.

FIG. 1B shows an overall view of the crystal structure of Compound A1bound to T790M-mutant EGFR. Compound A1 is shown in CPK form with carbonatoms and the ATP analog AMP-PNP is shown in stick form. The kinaseadopts an inactive conformation, and Compound A1 occupies an allostericsite created by outward displacement of the C-helix.

FIG. 1C shows the detailed view of interactions of Compound A1 with EGFRin the crystal structure of Compound A1 bound to T790M-mutant EGFR. Thecompound forms a hydrogen bond with Asp855 in the “DFG” segment of thekinase (dashed line), and the aminothiazole group extends between activesite residue Lys745 and the mutant gatekeeper Met790. A number ofhydrophobic residues contact the phenyl and oxindole “blades” of thecompound.

FIG. 2A is a graph showing EGFR activity in wild type and mutant EGFRkinases when treated with various concentrations of Compound A1 using 10μM ATP and 0.5 μM EGFR kinase (wild type, L858R, T790M, or L858R/T790M)and 1.25 mM poly[Glu₄Tyr] as a peptide substrate.

FIG. 2B is a graph showing EGFR activity in wild type and mutant EGFRkinases when treated with various concentrations of Compound A1 using 1mM ATP and 0.5 LM EGFR kinase (wild type, L858R, T790M, or L858R/T790M)and 1.25 mM poly[Glu₄Tyr] as a peptide substrate.

FIG. 3A shows structure of Compound A1 in complex with EGFR.

FIG. 3B shows structure of lapatinib bound to EGFR (PDB ID 1XKK).Lapatinib also binds an inactive conformation of the kinase. Like otheranilinoquinazoline inhibitors it occupies the ATP site, but it alsoextends into the allosteric pocket occupied by Compound A1. Note that itplaces phenyl groups in positions similar to those occupied by theaminothiazole and phenyl substituents of Compound A1.

FIG. 3C shows structure of MEK1 kinase bound to allosteric MEK1inhibitor GDC0973 (Cobimetinib). GDC0973 and other allosteric MEKinhibitors occupy a pocket created by displacement of the C-helix in theinactive conformation of the kinase. Most allosteric MEK inhibitors makehydrogen bond interactions with the γ-phosphate group of ATP that areimportant for their potency. The allosteric EGFR inhibitors describedherein bind in a generally analogous location in EGFR, but lack anyclear structural similarity to MEK inhibitors and do not contact theγ-phosphate group of ATP.

FIG. 4 is a graph showing EGFR activity in cells expressing EGFRT790M/L858R treated with 1 μg/mL cetuximab.

FIG. 5 is a western blot showing the levels of pEGFR, EGFR, pAkt, Akt,pErk, Erk, and tubulin in cells expressing EGFR T790M/L858R after a8-hour treatment with Compound I-126, in the absence or presence ofcetuximab.

DETAILED DESCRIPTION OF THE DISCLOSURE

Compounds of the Disclosure

A first aspect of the disclosure relates to compounds of Formula (I′):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein:

R₁ is (C₆-C₁₀) aryl, or heteroaryl comprising one or two 5- to7-membered rings and 1-4 heteroatoms selected from N, O, and S, whereinthe aryl and heteroaryl are each optionally substituted with one or moreR₁₁;

each R₁₁ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, OH, CN,C(O)R₁₃, C(O)OR₁₃, C(O)NR₁₃R₁₄, NR₁₃R₁₄, (C₃-C₇) cycloalkyl,heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, (C₆-C₁₀) aryl, and heteroaryl comprising oneor two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O,and S, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroarylare each optionally substituted with one or more R₁₂;

each R₁₂ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, OH, CN,(C₃-C₇) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S, (C₆-C₁₀) aryl, and heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the aryl and heteroaryl are eachoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, (C₃-C₇)cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S;

each R₁₃ is independently selected from H, (C₁-C₄) alkyl, (C₃-C₇)cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl,and heterocyclyl are each optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl, halogen, OH,NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, and heterocyclyl comprising a5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;

each R₁₄ is independently H or (C₁-C₃) alkyl;

R₂ is H or (C₁-C₃) alkyl;

R₃ is H or (C₁-C₃) alkyl;

R₄ is (C₁-C₃) alkyl or

X₁ is N or CR₆;

R₆ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, NO₂, NH₂, (CH₂)_(q)OH, S(O)_(r)R₂₃, or CN;

each R₇ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, NH₂, (CH₂)_(q)OH,S(O)_(r)R₂₃, and CN;

R₅ is NR₁₅R₁₆;

R_(5′) is H or (C₁-C₄) alkyl;

R₁₅ is H or (C₁-C₃) alkyl; R₁₆ is (C₆-C₁₀) aryl, or heteroarylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S, wherein the aryl and heteroaryl are each optionallysubstituted with one or more R₁₈; or

R₁₅ and R₁₆ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl optionally comprising 1 or 2additional heteroatoms selected from N, O, and S and optionallysubstituted with one or more oxo groups, wherein the heterocyclyl isfused with a phenyl ring which is optionally substituted with one ormore R₁₉;

each R₁₈ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(O)O(C₁-C₄) alkyl, NO₂,C(O)NH(C₁-C₄) alkyl, NH₂, NH(C₁-C₄) alkyl, and N((C₁-C₄) alkyl)₂,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from halogen, OH, NH₂, NH(C₁-C₄)alkyl, and N((C₁-C₄) alkyl)₂;

each R₁₉ is independently selected from halogen, O(CH₂)₁₋₃—OH, (C₃-C₇)cycloalkyl, (C₄-C₇) cycloalkenyl, (C₆-C₁₀) aryl, NH—(C₆-C₁₀) aryl, andheteroaryl comprising one or two 5- to 7-membered ring and 1-4heteroatoms selected from N, O, and S, wherein the aryl and heteroarylare each optionally substituted with one or more R₂₀; or

two R₁₉ together with the atoms to which they are attached form a(C₆-C₁₀) aryl optionally substituted with one or more R₂₀;

each R₂₀ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(O)OH, C(O)O(C₁-C₄)alkyl, C(O)NR₂₁R₂₂, O(CH₂)₁₋₃—OH, NH₂, OH, CN, O(CH₂)₀₋₃—(C₆-C₁₀) aryl,and (CH₂)₀₋₃-heterocyclyl which comprises a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, S(O)₂NH₂,(CH₂)_(s)OH, C(O)(CH₂)_(s)OH, and C(O)O(C₁-C₄) alkyl);

R₂₁ is H or (C₁-C₃) alkyl;

R₂₂ is H or (C₁-C₄) alkyl optionally substituted with one or moresubstituents independently selected from NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄)alkyl)₂, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S; or

R₂₁ and R₂₂ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl optionally containing 1-2additional heteroatoms selected from N, O, and S;

R₂₃ is H or NH₂;

m and n are each independently 0 or 1;

each r and each q are independently 0, 1, or 2;

each s is 1 or 2; and

p is 0, 1, 2, 3 or 4;

provided that when m is 0, n is 0, p is 0, R₁₅ and R₁₆ together with thenitrogen atom to which they are attached form an unsubstitutedisoindolinone, and R₆ is H, then R₁ is not

and

provided that R₄ is not 4-fluoro-2-hydroxyphenyl.

(1a) In some embodiments of Formula (I′), R₂ is H.

(1b) In some embodiments of Formula (I′), R₂ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂ is methyl.In other embodiments, R₂ is ethyl.

(2a) In some embodiments of Formula (I′), R₃ is H.

(2b) In some embodiments of Formula (I′), R₃ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₃ is methyl.In other embodiments, R₃ is ethyl.

(3a) In some embodiments of Formula (I′), R₄ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₄ is methyl.In other embodiments, R₄ is ethyl.

(3b) In some embodiments of Formula (I′), R₄ is

(e.g., phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl).

(4a) In some embodiments of Formula (I′), X₁ is N.

(4b) In some embodiments of Formula (I′), X₁ is CR₆.

(5a) In some embodiments of Formula (I′), R₆ is H.

(5b) In some embodiments of Formula (I′), R₆ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl).

(5c) In some embodiments of Formula (I′), R₆ is (C₁-C₄) haloalkyl (e.g.,CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃).

(5d) In some embodiments of Formula (I′), R₆ is (C₁-C₄) alkoxy (e.g.,methoxy, ethoxy, propoxy, or butoxy).

(5e) In some embodiments of Formula (I′), R₆ is halogen (e.g., F, Cl, Bror I). In other embodiments, R₆ is F or Cl. In further embodiments, R₆is F.

(5f) In some embodiments of Formula (I′), R₆ is NO₂, NH₂, (CH₂)_(q)OH,S(O)_(r)R₂₃, or CN. In further embodiments, R₆ is (CH₂)_(q)OH,S(O)_(r)R₂₃, NO₂, or NH₂.

(6a) In some embodiments of Formula (I′), at least one R₇ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl).

(6b) In some embodiments of Formula (I′), at least one R₇ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃).

(6c) In some embodiments of Formula (I′), at least one R₇ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(6d) In some embodiments of Formula (I′), at least one R₇ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₇ is F orCl. In further embodiments, at least one R₇ is F.

(6e) In some embodiments of Formula (I′), at least one R₇ is NO₂, NH₂,(CH₂)_(q)OH, S(O)_(r)R₂₃, or CN. In further embodiments, at least one R₇is (CH₂)_(q)OH, S(O)_(r)R₂₃, NO₂, or NH₂.

(6f) In some embodiments of Formula (I′), at least one R₇ is halogen(e.g., F, Cl, Br or I) and at least one R₇ is OH.

(6g) In some embodiments of Formula (I′), one R₇ is halogen (e.g., F,Cl, Br or I) and one R₇ is OH.

(7a) In some embodiments of Formula (I′), R₅ is NR₁₅R₁₆.

(7b) In some embodiments of Formula (I′), R₅ is N(H)-phenyl.

(8a) In some embodiments of Formula (I′), R₁₅ is H.

(8b) In some embodiments of Formula (I′), R₁₅ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₁₅ ismethyl. In other embodiments, R₁₅ is ethyl.

(9a) In some embodiments of Formula (I′), R₁₆ is (C₆-C₁₀) aryloptionally substituted with one or more R₁₈. In other embodiments, R₁₆is phenyl optionally substituted with one or more R₁₈. In furtherembodiments, R₁₆ is phenyl optionally substituted with one to three R₁₈.

(9b) In some embodiments of Formula (I′), R₁₆ is heteroaryl comprising a5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S(e.g., pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl,oxadiazolyl, dioxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,dithiazolyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl,etc.) optionally substituted with one or more R₁₈. In furtherembodiments, R₁₆ is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl optionallysubstituted with one or more R₁₈.

(9c) In some embodiments of Formula (I′), R₁₅ and R₁₆ together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclyl optionally comprising 1 or 2 additional heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, etc.) and optionallysubstituted with one or more oxo groups. In other embodiments, R₁₅ andR₁₆ together with the nitrogen atom to which they are attached form

(10a) In some embodiments of Formula (I′), at least one R₁₈ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl) optionallysubstituted with one or more substituents independently selected fromhalogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), and N((C₁-C₄)alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is methyl or ethyloptionally substituted with one or more substituents independentlyselected from halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl(e.g., methylamino, ethylamino, propylamino, or butylamino), andN((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is methyl orethyl.

(10b) In some embodiments of Formula (I′), at least one R₁₈ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(10c) In some embodiments of Formula (I′), at least one R₁₈ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃).

(10d) In some embodiments of Formula (I′), at least one R₁₈ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₁₈ is F orBr.

(10e) In some embodiments of Formula (I′), at least one R₁₈ isC(O)O(C₁-C₄) alkyl or C(O)NH(C₁-C₄) alkyl, wherein the alkyl isoptionally substituted with one or more substituents independentlyselected from halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl(e.g., methylamino, ethylamino, propylamino, or butylamino), andN((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is C(O)O(C₁-C₄)alkyl. In other embodiments, at least one R₁₈ is C(O)NH(C₁-C₄) alkyloptionally substituted with one or more OH. In other embodiments, atleast one R₁₈ is C(O)OCH₃. In other embodiments, at least one R₁₈ isC(O)N(H)CH₂CH(OH)CH₂OH.

(10f) In some embodiments of Formula (I′), at least one R₁₈ is NO₂, NH₂,NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), or N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), wherein the alkyl is optionallysubstituted with one or more substituents independently selected fromhalogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), and N((C₁-C₄)alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is NO₂.

(11a) In some embodiments of Formula (I′), at least one R₁₉ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₁₉ is F, Cl,or Br. In other embodiments, at least one R₁₉ is F. In otherembodiments, at least one R₁₉ is Cl. In other embodiments, at least oneR₁₉ is Br.

(11b) In some embodiments of Formula (I′), at least one R₁₉ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl).

(11c) In some embodiments of Formula (I′), at least one R₁₉ is (C₄-C₇)cycloalkenyl (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, orcycloheptenyl). In other embodiments, at least one R₁₉ is cyclohexenyl.

(11d) In some embodiments of Formula (I′), at least one R₁₉ is (C₆-C₁₀)aryl optionally substituted with one or more R₂₀. In other embodiments,at least one R₁₉ is phenyl optionally substituted with one or more R₂₀.In other embodiments, at least one R₁₉ is phenyl optionally substitutedwith one to three R₂₀. In other embodiments, at least one R₁₉ is phenyl.

(11e) In some embodiments of Formula (I′), at least one R₁₉ isNH—(C₆-C₁₀) aryl optionally substituted with one or more R₂₀. In otherembodiments, at least one R₁₉ is NH-phenyl optionally substituted withone or more R₂₀. In other embodiments, at least one R₁₉ is NH-phenyloptionally substituted with one to three R₂₀. In other embodiments, atleast one R₁₉ is NH-phenyl.

(11f) In some embodiments of Formula (I′), at least one R₁₉ isheteroaryl comprising one or two 5- to 7-membered rings and 1-4heteroatoms selected from N, O, and S (e.g., pyrrolyl, pyrazolyl,imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl,pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, indazolyl,quinolinyl, isoquinolinyl, benzothiazolyl, benzoimidazolyl,benzooxazolyl, thiazolopyridinyl, pyrrolopyridinyl, pyrazolopyrimidinyl,etc.) optionally substituted with one or more R₂₀. In other embodiments,at least one R₁₉ is pyrazolyl, thiophenyl, pyridinyl, pyrimidinyl,indolyl, or quinolinyl optionally substituted with one or more R₂₀.

(11g) In some embodiments of Formula (I′), at least one R₁₉ isO(CH₂)₁₋₃—OH. In other embodiments, at least one R₁₉ is O(CH₂)—OH. Inother embodiments, at least one R₁₉ is O(CH₂)₂—OH. In other embodiments,at least one R₁₉ is O(CH₂)₃—OH.

(11h) In some embodiments of Formula (I′), two R₁₉ together with theatoms to which they are attached form a (C₆-C₁₀) aryl optionallysubstituted with one or more R₂₀. In other embodiments, two R₁₉ togetherwith the atoms to which they are attached form a phenyl optionallysubstituted with one or more R₂₀. In other embodiments, two R₁₉ togetherwith the atoms to which they are attached form a phenyl.

(12a) In some embodiments of Formula (I′), at least one R₂₀ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl). In furtherembodiments, at least one R₂₀ is methyl or ethyl.

(12b) In some embodiments of Formula (I′), at least one R₂₀ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy). In furtherembodiments, at least one R₂₀ is methoxy.

(12c) In some embodiments of Formula (I′), at least one R₂₀ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃). In further embodiments, at least one R₂₀ is CF₃ orOCF₃.

(12d) In some embodiments of Formula (I′), at least one R₂₀ is halogen(e.g., F, Cl, Br or I). In further embodiments, at least one R₂₀ is F.

(12e) In some embodiments of Formula (I′), at least one R₂₀ is C(O)OH orC(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl). Infurther embodiments, at least one R₂₀ is C(O)OH or C(O)OCH₃.

(12f) In some embodiments of Formula (I′), at least one R₂₀ is NH₂, OH,or CN.

(12g) In some embodiments of Formula (I′), at least one R₂₀ isC(O)NR₂₁R₂₂.

(12h) In some embodiments of Formula (I′), at least one R₂₀ isO(CH₂)₀₋₃—(C₆-C₁₀) aryl. In further embodiments, at least one R₂₀ isOCH₂-phenyl.

(12i) In some embodiments of Formula (I′), at least one R₂₀ is(CH₂)₀₋₃-heterocyclyl which comprises a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the heterocyclyl isselected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl,triazolidinyl, oxazolidinyl, isoxazolidinyl, oxadiazolidinyl,dioxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl,dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.,and is optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), S(O)₂NH₂, (CH₂)_(s)OH (e.g., CH₂OH,CH₂CH₂OH), C(O)(CH₂)_(s)OH (e.g., C(O)CH₂OH, C(O)CH₂CH₂OH), andC(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl). In other embodiments, at least one R₂₀ is(CH₂)₀₋₁-heterocycle optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl (e.g., methyl,ethyl, propyl, i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, propoxy, or butoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, orCF₃), (C₁-C₄) haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g.,F, Cl, Br or I), and C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl). In other embodiments, at leastone R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl, pyrrolidinyl, morpholinyl,or piperazinyl wherein the pyrrolidinyl, morpholinyl, and piperazinylare each optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), S(O)₂NH₂, (CH₂)_(s)OH (e.g., CH₂OH,CH₂CH₂OH), C(O)(CH₂)_(s)OH (e.g., C(O)CH₂OH, C(O)CH₂CH₂OH), andC(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, or t-butyl). In other embodiments, at least one R₂₀ isCH₂-pyrrolidinyl, CH₂-piperazinyl, pyrrolidinyl, morpholinyl, orpiperazinyl, wherein the pyrrolidinyl, morpholinyl, and piperazinyl areeach optionally substituted with one or more (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl), N((C₁-C₄) alkyl)₂ (e.g.,dimethylamino, diethylamino, dipropylamino, or dibutylamino), S(O)₂NH₂,(CH₂)_(s)OH (e.g., CH₂OH, CH₂CH₂OH), C(O)(CH₂)_(s)OH (e.g., C(O)CH₂OH,C(O)CH₂CH₂OH), or C(O)O(C₁-C₄)alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl). In other embodiments, at leastone R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl, pyrrolidinyl, morpholinyl,or piperazinyl, wherein the pyrrolidinyl, morpholinyl, and piperazinylare each optionally substituted with one or more (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl) or C(O)O(C₁-C₄)alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl). In otherembodiments, at least one R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl,morpholinyl, or piperazinyl, wherein the pyrrolidinyl, morpholinyl, andpiperazinyl are optionally methyl, ethyl, N(methyl)₂, S(O)₂NH₂,(CH₂)₂OH, C(O)(CH₂)OH, or C(O)O-t-butyl. In other embodiments, at leastone R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl, morpholinyl, orpiperazinyl, wherein the pyrrolidinyl, morpholinyl, and piperazinyl areoptionally methyl, ethyl, or C(O)O-t-butyl.

(12j) In some embodiments of Formula (I′), at least one R₂₀ isO(CH₂)₁₋₃—OH. In other embodiments, at least one R₂₀ is O(CH₂)—OH. Inother embodiments, at least one R₂₀ is O(CH₂)₂—OH. In other embodiments,at least one R₂₀ is O(CH₂)₃—OH.

(13a) In some embodiments of Formula (I′), R₂₁ is H.

(13b) In some embodiments of Formula (I′), R₂₁ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂₁ ismethyl. In other embodiments, R₂₁ is ethyl.

(14a) In some embodiments of Formula (I′), R₂₂ is H.

(14b) In some embodiments of Formula (I′), R₂₂ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl) optionally substituted withone or more substituents independently selected from NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, triazolidinyl, oxazolidinyl,isoxazolidinyl, oxadiazolidinyl, dioxazolidinyl, thiazolidinyl,isothiazolidinyl, thiadiazolidinyl, dithiazolidinyl, piperidinyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, dioxanyl,etc.). In other embodiments, R₂₂ is (C₁-C₄) alkyl (e.g., methyl, ethyl,propyl, i-propyl, or butyl) optionally substituted with one to twosubstituents independently selected from NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄)alkyl)₂, and 6-membered heterocycle comprising 1-3 heteroatoms selectedfrom N, O, and S. In further embodiments, R₂₂ is ethyl, propyl, or butyloptionally substituted with dimethylamino, diethylamino, or morpholinyl.

(14c) In some embodiments of Formula (I′), R₂₁ and R₂₂ together with thenitrogen atom to which they are attached form a 5-membered heterocyclyloptionally containing 1-2 additional heteroatoms selected from N, O, andS. In other embodiments, R₂₁ and R₂₂ together with the nitrogen atom towhich they are attached form a 6-membered heterocycle optionallycontaining 1-2 additional heteroatoms selected from N, O, and S. Infurther embodiments, R₂₁ and R₂₂ together with the nitrogen atom towhich they are attached form a morpholinyl.

(15a) In some embodiments of Formula (I′), R₁ is (C₆-C₁₀) aryloptionally substituted with one or more R₁₁. In other embodiments, R₁ isphenyl optionally substituted with one or more R₁₁.

(15b) In some embodiments of Formula (I′), R₁ is heteroaryl comprisingone or two 5- to 7-membered rings and 1-4 heteroatoms selected from N,O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl,isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl, isothiazolyl,thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl, pyridazinyl,pyrimidinyl, triazinyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl,quinolinyl, thiazolopyridinyl, pyrazolopyrimidinyl, etc.) optionallysubstituted with one or more R₁₁. In other embodiments, R₁ is heteroarylcomprising a 5-membered ring and 1-3 heteroatoms selected from N, O, andS, optionally substituted with one or more R₁₁. In other embodiments, R₁is heteroaryl comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, optionally substituted with one or more R₁₁. In otherembodiments, R₁ is heteroaryl comprising a 5-membered ring fused with a6-membered ring and 1-4 heteroatoms selected from N, O, and S,optionally substituted with one or more R₁₁. In other embodiments, R₁ isselected from:

wherein each moiety is optionally substituted with one or more R₁₁. Inother embodiments, R₁ is selected from:

wherein each moiety is optionally substituted with one or more R₁₁. Inother embodiments, R₁ is

(16a) In some embodiments of Formula (I′), at least one R₁₁ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl) optionallysubstituted with one or more R₁₂. In other embodiments, at least one R₁₁is methyl. In other embodiments, at least one R₁₁ is propyl optionallysubstituted with one to two R₁₂.

(16b) In some embodiments of Formula (I′), at least one R₁₁ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃). In further embodiments, at least one R₁₁ is CF₃.

(16c) In some embodiments of Formula (I′), at least one R₁₁ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(16d) In some embodiments of Formula (I′), at least one R₁₁ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₁₁ is F. Inother embodiments, at least one R₁₁ is Cl. In other embodiments, atleast one R₁₁ is Br.

(16e) In some embodiments of Formula (I′), at least one R₁₁ is NO₂, OH,or CN.

(16f) In some embodiments of Formula (I′), at least one R₁₁ is C(O)R₁₃or C(O)OR₁₃. In other embodiments, at least one R₁₁ is C(O)OCH₂CH₃.

(16g) In some embodiments of Formula (I′), at least one R₁₁ isC(O)NR₁₃R₁₄ or NR₁₃R₁₄. In other embodiments, at least one R₁₁ isC(O)NR₁₃R₁₄ or NH₂.

(16h) In some embodiments of Formula (I′), at least one R₁₁ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl) optionally substituted with one or more R₁₂. In furtherembodiments, at least one R₁₁ is cyclopropyl.

(16i) In some embodiments of Formula (I′), at least one R₁₁ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)optionally substituted with one or more R₁₂.

(16j) In some embodiments of Formula (I′), at least one R₁₁ is (C₆-C₁₀)aryl optionally substituted with one or more R₁₂. In furtherembodiments, at least one R₁₁ is phenyl optionally substituted with oneor more R₁₂.

(16k) In some embodiments of Formula (I′), at least one R₁₁ isheteroaryl comprising one or two 5- to 7-membered rings and 1-4heteroatoms selected from N, O, and S (e.g., pyrrolyl, pyrazolyl,imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl,pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, benzothiazolyl,benzoimidazolyl, benzooxazolyl, quinolinyl, etc.) comprising 1-3heteroatoms selected from N, O, and S, optionally substituted with oneor more R₁₂. In other embodiments, at least one R₁₁ is heteroarylcomprising a 6-membered ring (e.g., pyridinyl, pyridazinyl, pyrimidinyl,triazinyl, etc.) optionally substituted with one or more R₁₂. In otherembodiments, at least one R₁₁ is pyridinyl optionally substituted withone or more R₁₂. In further embodiments, at least one R₁₁ is pyridinyl.

(17a) In some embodiments of Formula (I′), at least one R₁₂ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl).

(17b) In some embodiments of Formula (I′), at least one R₁₂ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃).

(17c) In some embodiments of Formula (I′), at least one R₁₂ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(17d) In some embodiments of Formula (I′), at least one R₁₂ is halogen(e.g., F, Cl, Br or I).

(17e) In some embodiments of Formula (I′), at least one R₁₂ is NO₂, OH,or CN.

(17f) In some embodiments of Formula (I′), at least one R₁₂ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl).

(17g) In some embodiments of Formula (I′), at least one R₁₂ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)comprising 1-3 heteroatoms selected from N, O, and S. In otherembodiments, at least one R₁₂ is piperidinyl, piperazinyl, ormorpholinyl. In further embodiments, at least one R₁₂ is morpholinyl.

(17h) In some embodiments of Formula (I′), at least one R₁₂ is (C₆-C₁₀)aryl optionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, orbutyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy),(C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄) haloalkoxy (e.g.,OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br or I), NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), (C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl), and heterocyclyl comprising a5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S(e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl,oxazolidinyl, isoxazolidinyl, oxadiazolidinyl, dioxazolidinyl,thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, dithiazolidinyl,piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl,dioxanyl, azepinyl, diazepinyl, etc.).

(17i) In some embodiments of Formula (I′), R₁₂ is heteroaryl comprisingone or two 5- to 7-membered rings and 1-4 heteroatoms selected from N,O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl,isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl, isothiazolyl,thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl, pyridazinyl,pyrimidinyl, triazinyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl,quinolinyl, etc.) optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), (C₃-C₇) cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl), and heterocyclylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,triazolidinyl, oxazolidinyl, isoxazolidinyl, oxadiazolidinyl,dioxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl,dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl,etc.). In other embodiments, at least one R₁₂ is heteroaryl comprising a5-membered ring fused with a 6-membered ring and 1-4 heteroatomsselected from N, O, and S, optionally substituted with one or moresubstituents independently selected from NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), and(C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl).

(18a) In some embodiments of Formula (I′), at least one R₁₃ is H.

(18b) In some embodiments of Formula (I′), at least one R₁₃ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl) optionallysubstituted with one or more substituents independently selected fromhalogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), andheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl,etc.). In other embodiments, at least one R₁₃ is methyl, ethyl, orpropyl. In other embodiments, at least one R₁₃ is ethyl, propyl, orbutyl, wherein the ethyl, propyl, and butyl are optionally substitutedwith one to two substituents independently selected from NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocycle comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S. In other embodiments, atleast one R₁₃ is ethyl, propyl, or butyl, wherein the ethyl, propyl, andbutyl are optionally substituted with one to two substituentsindependently selected from N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino) and heterocycle comprisinga 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S.In other embodiments, at least one R₁₃ is ethyl, propyl, or butyl,wherein the ethyl, propyl, and butyl are optionally substituted with oneto two substituents independently selected from dimethylamino andheterocycle comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S. In other embodiments, at least one R₁₃ is ethyl,propyl, or butyl wherein the ethyl, propyl, and butyl are optionallysubstituted with one to two substituents independently selected fromdimethylamino, morpholinyl, piperidinyl or piperazinyl. In furtherembodiments, at least one R₁₃ is ethyl, propyl, or butyl wherein theethyl, propyl, and butyl are optionally substituted with dimethylaminoor morpholinyl.

(18c) In some embodiments of Formula (I′), at least one R₁₃ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl).

(18d) In some embodiments of Formula (I′), at least one R₁₃ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)optionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, orbutyl), halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), andheterocycle comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S. In other embodiments, at least one R₁₃ isheterocycle comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocycle comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S. In other embodiments, atleast one R₁₃ is morpholinyl, piperidinyl, or piperazinyl, wherein themorpholinyl, piperidinyl, and piperazinyl are optionally substitutedwith one or more substituents independently selected from (C₁-C₄) alkyl(e.g., methyl, ethyl, propyl, i-propyl, or butyl), halogen (e.g., F, Cl,Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino,propylamino, or butylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), and heterocyclecomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S. In other embodiments, at least one R₁₃ is morpholinyl,piperidinyl, or piperazinyl, wherein the morpholinyl, piperidinyl, andpiperazinyl are optionally substituted with (C₁-C₄) alkyl (e.g., methyl,ethyl, propyl, i-propyl, or butyl), halogen (e.g., F, Cl, Br or I), OH,NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), or heterocycle comprising a 5- to7-membered ring and 1-3 heteroatoms selected from N, O, and S. In otherembodiments, at least one R₁₃ is morpholinyl, piperidinyl, orpiperazinyl, wherein the morpholinyl, piperidinyl, and piperazinyl areoptionally substituted with (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), or heterocycle comprisinga 6-membered ring and 1-3 heteroatoms selected from N, O, and S. Infurther embodiments, at least one R₁₃ is morpholinyl, piperidinyl, orpiperazinyl, wherein the morpholinyl, piperidinyl, and piperazinyl areoptionally substituted with methyl, dimethylamino, or morpholinyl.

(19a) In some embodiments of Formula (I′), at least one R₁₄ is H.

(19b) In some embodiments of Formula (I′), at least one R₁₄ is (C₁-C₃)alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

(20a) In some embodiments of Formula (I′), m is 0 or 1.

(20b) In some embodiments of Formula (I′), m is 0.

(20c) In some embodiments of Formula (I′), m is 1.

(21a) In some embodiments of Formula (I′), n is 0 or 1.

(21b) In some embodiments of Formula (I′), n is 0.

(21c) In some embodiments of Formula (I′), n is 1.

(22a) In some embodiments of Formula (I′), p is 0, 1, 2, 3, or 4. Inother embodiments, p is 0, 1, 2, or 3. In other embodiments, p is 0, 1,or 2.

(22b) In some embodiments of Formula (I′), p is 0 or 1.

(22c) In some embodiments of Formula (I′), p is 1 or 2. In otherembodiments, p is 2 or 3.

(22d) In some embodiments of Formula (I′), p is 0. In other embodiments,p is 1. In other embodiments, p is 2. In other embodiments, p is 3. Inother embodiments, p is 4.

(23a) In some embodiments of Formula (I′), R₅ is H.

(23b) In some embodiments of Formula (I′), R_(5′) is (C₁-C₄) alkyl(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl).

(24a) In some embodiments of Formula (I′), R₂₃ is H.

(24b) In some embodiments of Formula (I′), R₂₃ is NH₂.

(25a) In some embodiments of Formula (I′), r is 0 or 1. In otherembodiments, r is 1 or 2.

(25b) In some embodiments of Formula (I′), r is 0.

(25c) In some embodiments of Formula (I′), r is 1.

(25d) In some embodiments of Formula (I′), r is 2.

(26a) In some embodiments of Formula (I′), q is 0 or 1. In otherembodiments, q is 1 or 2.

(26b) In some embodiments of Formula (I′), q is 0.

(26c) In some embodiments of Formula (I′), q is 1.

(26d) In some embodiments of Formula (I′), q is 2.

(27a) In some embodiments of Formula (I′), s is 1.

(27b) In some embodiments of Formula (I′), s is 2.

In some embodiments of Formula (I′), R₅ is

wherein q is 0, 1, 2, 3, or 4.

In some embodiments of Formula (I′), each of the substituents definedfor any one of X₁, R₁, R₂, R₃, R₄, R₅, R_(5′), R₆, R₇, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, m, n, p, q, r, and s can becombined with any of the substituents defined for the remainder of X₁,R₁, R₂, R₃, R₄, R₅, R_(5′), R₆, R₇, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, m, n, p, q, r, and s.

(28) In some embodiments, R₁ is as defined in (15a).

(29) In some embodiments, R₁ is as defined in (15a) and m is as definedin (20b).

(30) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), and R₂ is as defined in (1a).

(31) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21b).

(32) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3a).

(33) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(34) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3b).

(35) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(36) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(37) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR₆ is as defined in (5a).

(38) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21c).

(39) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3a).

(40) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(41) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3b).

(42) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(43) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(44) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR₆ is as defined in (5a).

(45) In some embodiments, R₁ is as defined in (15a) and m is as definedin (20c).

(46) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), and R₂ is as defined in (1a).

(47) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), and R₃ is as defined in (2a).

(48) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21b).

(49) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3a).

(50) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(51) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3b).

(52) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(53) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(54) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

(55) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21c).

(56) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3a).

(57) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(58) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3b).

(59) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(60) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(61) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

(62) In some embodiments, R₁ is as defined in (15b).

(63) In some embodiments, R₁ is as defined in (15b) and m is as definedin (20b).

(64) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), and R₂ is as defined in (1a).

(65) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21b).

(66) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3a).

(67) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(68) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3b).

(69) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(70) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(71) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR₆ is as defined in (5a).

(72) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21c).

(73) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3a).

(74) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(75) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3b).

(76) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(77) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(78) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR₆ is as defined in (5a).

(79) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c).

(80) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), and R₂ is as defined in (1a).

(81) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), and R₃ is as defined in (2a).

(82) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21b).

(83) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3a).

(84) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(85) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3b).

(86) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(87) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(88) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

(89) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21c).

(90) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3a).

(91) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(92) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3b).

(93) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(94) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(95) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

(96) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4a).

(97) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), R₆is as defined in (5a), and R_(5′) is as defined in (23a).

(98) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), R₆is as defined in (5a), and R_(5′) is as defined in (23b).

In some embodiments, the compounds of Formula (I′) have the structure ofFormula (I):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein:

R₁ is (C₆-C₁₀) aryl, or heteroaryl comprising one or two 5- to7-membered rings and 1-4 heteroatoms selected from N, O, and S, whereinthe aryl and heteroaryl are each optionally substituted with one or moreR₁₁;

each R₁₁ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, OH, CN,C(O)R₁₃, C(O)OR₁₃, C(O)NR₁₃R₁₄, NR₁₃R₁₄, (C₃-C₇) cycloalkyl,heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, (C₆-C₁₀) aryl, and heteroaryl comprising oneor two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O,and S, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroarylare each optionally substituted with one or more R₁₂;

each R₁₂ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, OH, CN,(C₃-C₇) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S, (C₆-C₁₀) aryl, and heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the aryl and heteroaryl are eachoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, (C₃-C₇)cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S;

each R₁₃ is independently selected from H, (C₁-C₄) alkyl, (C₃-C₇)cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl,and heterocyclyl are each optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl, halogen, OH,NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, and heterocyclyl comprising a5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;

each R₁₄ is independently H or (C₁-C₃) alkyl;

R₂ is H or (C₁-C₃) alkyl;

R₃ is H or (C₁-C₃) alkyl;

R₄ is (C₁-C₃) alkyl or

X₁ is N or CR₆;

R₆ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, NO₂, NH₂, OH, or CN;

each R₇ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, NH₂, OH, and CN;

R₅ is NR₁₅R₁₆;

R₁₅ is H or (C₁-C₃) alkyl;

R₁₆ is (C₆-C₁₀) aryl, or heteroaryl comprising a 5- to 7-membered ringand 1-3 heteroatoms selected from N, O, and S, wherein the aryl andheteroaryl are each optionally substituted with one or more R₁₈; or

R₁₅ and R₁₆ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl optionally comprising 1 or 2additional heteroatoms selected from N, O, and S and optionallysubstituted with one or more oxo groups, wherein the heterocyclyl isfused with a phenyl ring which is optionally substituted with one ormore R₁₉;

each R₁₈ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(O)O(C₁-C₄) alkyl, NO₂,C(O)NH(C₁-C₄) alkyl, NH₂, NH(C₁-C₄) alkyl, and N((C₁-C₄) alkyl)₂,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from halogen, OH, NH₂, NH(C₁-C₄)alkyl, and N((C₁-C₄) alkyl)₂;

each R₁₉ is independently selected from halogen, (C₃-C₇) cycloalkyl,(C₄-C₇) cycloalkenyl, (C₆-C₁₀) aryl, NH—(C₆-C₁₀) aryl, and heteroarylcomprising one or two 5- to 7-membered ring and 1-4 heteroatoms selectedfrom N, O, and S, wherein the aryl and heteroaryl are each optionallysubstituted with one or more R₂₀;

each R₂₀ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(O)OH, C(O)O(C₁-C₄)alkyl, C(O)NR₂₁R₂₂, NH₂, OH, CN, O(CH₂)₀₋₃—(C₆-C₁₀) aryl, and(CH₂)₀₋₃-heterocyclyl which comprises a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, and C(O)O(C₁-C₄) alkyl);

R₂₁ is H or (C₁-C₃) alkyl;

R₂₂ is H or (C₁-C₄) alkyl optionally substituted with one or moresubstituents independently selected from NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄)alkyl)₂, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S; or

R₂₁ and R₂₂ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl optionally containing 1-2additional heteroatoms selected from N, O, and S;

-   -   m and n are each independently 0 or 1; and    -   p is 0, 1, 2, 3 or 4;    -   provided that when m is 0, n is 0, p is 0, R₁₅ and R₁₆ together        with the nitrogen atom to which they are attached form an        unsubstituted isoindolinone, and R₆ is H, then R₁ is not

and

provided that R₄ is not 4-fluoro-2-hydroxyphenyl.

(1a) In some embodiments of Formula (I), R₂ is H.

(1b) In some embodiments of Formula (I), R₂ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂ is methyl.In other embodiments, R₂ is ethyl.

(2a) In some embodiments of Formula (I), R₃ is H.

(2b) In some embodiments of Formula (I), R₃ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₃ is methyl.In other embodiments, R₃ is ethyl.

(3a) In some embodiments of Formula (I), R₄ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₄ is methyl.In other embodiments, R₄ is ethyl.

(3b) In some embodiments of Formula (I), R₄ is

(e.g., phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl).

(4a) In some embodiments of Formula (I), X₁ is N.

(4b) In some embodiments of Formula (I), X₁ is CR₆.

(5a) In some embodiments of Formula (I), R₆ is H.

(5b) In some embodiments of Formula (I), R₆ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl).

(5c) In some embodiments of Formula (I), R₆ is (C₁-C₄) haloalkyl (e.g.,CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃).

(5d) In some embodiments of Formula (I), R₆ is (C₁-C₄) alkoxy (e.g.,methoxy, ethoxy, propoxy, or butoxy).

(5e) In some embodiments of Formula (I), R₆ is halogen (e.g., F, Cl, Bror I). In other embodiments, R₆ is F or Cl. In further embodiments, R₆is F.

(5f) In some embodiments of Formula (I), R₆ is NO₂, NH₂, OH, or CN. Infurther embodiments, R₆ is NO₂ or NH₂.

(6a) In some embodiments of Formula (I), at least one R₇ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl).

(6b) In some embodiments of Formula (I), at least one R₇ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃).

(6c) In some embodiments of Formula (I), at least one R₇ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(6d) In some embodiments of Formula (I), at least one R₇ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₇ is F orCl. In further embodiments, at least one R₇ is F.

(6e) In some embodiments of Formula (I), at least one R₇ is NO₂, NH₂,OH, or CN. In further embodiments, at least one R₇ is NO₂ or NH₂.

(6f) In some embodiments of Formula (I), at least one R₇ is halogen(e.g., F, Cl, Br or I) and at least one R₇ is OH.

(6g) In some embodiments of Formula (I), one R₇ is halogen (e.g., F, Cl,Br or I) and one R₇ is OH.

(7a) In some embodiments of Formula (I), R₅ is NR₁₅R₁₆.

(7b) In some embodiments of Formula (I), R₅ is N(H)-phenyl.

(8a) In some embodiments of Formula (I), R₁₅ is H.

(8b) In some embodiments of Formula (I), R₁₅ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₁₅ ismethyl. In other embodiments, R₁₅ is ethyl.

(9a) In some embodiments of Formula (I), R₁₆ is (C₆-C₁₀) aryl optionallysubstituted with one or more R₁₈. In other embodiments, R₁₆ is phenyloptionally substituted with one or more R₁₈. In further embodiments, R₁₆is phenyl optionally substituted with one to three R₁₈.

(9b) In some embodiments of Formula (I), R₁₆ is heteroaryl comprising a5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S(e.g., pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl,oxadiazolyl, dioxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,dithiazolyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl,etc.) optionally substituted with one or more R₁₈. In furtherembodiments, R₁₆ is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl optionallysubstituted with one or more R₁₈.

(9c) In some embodiments of Formula (I), R₁₅ and R₁₆ together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclyl optionally comprising 1 or 2 additional heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, etc.) and optionallysubstituted with one or more oxo groups. In other embodiments, R₁₅ andR₁₆ together with the nitrogen atom to which they are attached form

(10a) In some embodiments of Formula (I), at least one R₁₈ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl) optionallysubstituted with one or more substituents independently selected fromhalogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), and N((C₁-C₄)alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is methyl or ethyloptionally substituted with one or more substituents independentlyselected from halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl(e.g., methylamino, ethylamino, propylamino, or butylamino), andN((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is methyl orethyl.

(10b) In some embodiments of Formula (I), at least one R₁₈ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(10c) In some embodiments of Formula (I), at least one R₁₈ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃).

(10d) In some embodiments of Formula (I), at least one R₁₈ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₁₈ is F orBr.

(10e) In some embodiments of Formula (I), at least one R₁₈ isC(O)O(C₁-C₄) alkyl or C(O)NH(C₁-C₄) alkyl, wherein the alkyl isoptionally substituted with one or more substituents independentlyselected from halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl(e.g., methylamino, ethylamino, propylamino, or butylamino), andN((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is C(O)O(C₁-C₄)alkyl. In other embodiments, at least one R₁₈ is C(O)NH(C₁-C₄) alkyloptionally substituted with one or more OH. In other embodiments, atleast one R₁₈ is C(O)OCH₃. In other embodiments, at least one R₁₈ isC(O)N(H)CH₂CH(OH)CH₂OH.

(10f) In some embodiments of Formula (I), at least one R₁₈ is NO₂, NH₂,NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), or N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), wherein the alkyl is optionallysubstituted with one or more substituents independently selected fromhalogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), and N((C₁-C₄)alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino). In other embodiments, at least one R₁₈ is NO₂.

(11a) In some embodiments of Formula (I), at least one R₁₉ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₁₉ is F, Cl,or Br. In other embodiments, at least one R₁₉ is F. In otherembodiments, at least one R₁₉ is Cl. In other embodiments, at least oneR₁₉ is Br.

(11b) In some embodiments of Formula (I), at least one R₁₉ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl).

(11c) In some embodiments of Formula (I), at least one R₁₉ is (C₄-C₇)cycloalkenyl (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, orcycloheptenyl). In other embodiments, at least one R₁₉ is cyclohexenyl.

(11d) In some embodiments of Formula (I), at least one R₁₉ is (C₆-C₁₀)aryl optionally substituted with one or more R₂₀. In other embodiments,at least one R₁₉ is phenyl optionally substituted with one or more R₂₀.In other embodiments, at least one R₁₉ is phenyl optionally substitutedwith one to three R₂₀. In other embodiments, at least one R₁₉ is phenyl.

(11e) In some embodiments of Formula (I), at least one R₁₉ isNH—(C₆-C₁₀) aryl optionally substituted with one or more R₂₀. In otherembodiments, at least one R₁₉ is NH-phenyl optionally substituted withone or more R₂₀. In other embodiments, at least one R₁₉ is NH-phenyloptionally substituted with one to three R₂₀. In other embodiments, atleast one R₁₉ is NH-phenyl.

(11f) In some embodiments of Formula (I), at least one R₁₉ is heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl,isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl,pyridazinyl, pyrimidinyl, triazinyl, indolyl, quinolinyl, isoquinolinyl,benzothiazolyl, benzoimidazolyl, benzooxazolyl, thiazolopyridinyl,pyrazolopyrimidinyl, etc.) optionally substituted with one or more R₂₀.In other embodiments, at least one R₁₉ is pyrazolyl, thiophenyl,pyridinyl, pyrimidinyl, indolyl, or quinolinyl optionally substitutedwith one or more R₂₀.

(12a) In some embodiments of Formula (I), at least one R₂₀ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl). In furtherembodiments, at least one R₂₀ is methyl or ethyl.

(12b) In some embodiments of Formula (I), at least one R₂₀ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy). In furtherembodiments, at least one R₂₀ is methoxy.

(12c) In some embodiments of Formula (I), at least one R₂₀ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃). In further embodiments, at least one R₂₀ is CF₃ orOCF₃.

(12d) In some embodiments of Formula (I), at least one R₂₀ is halogen(e.g., F, Cl, Br or I). In further embodiments, at least one R₂₀ is F.

(12e) In some embodiments of Formula (I), at least one R₂₀ is C(O)OH orC(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl). Infurther embodiments, at least one R₂₀ is C(O)OH or C(O)OCH₃.

(12f) In some embodiments of Formula (I), at least one R₂₀ is NH₂, OH,or CN.

(12g) In some embodiments of Formula (I), at least one R₂₀ isC(O)NR₂₁R₂₂.

(12h) In some embodiments of Formula (I), at least one R₂₀ isO(CH₂)₀₋₃—(C₆-C₁₀) aryl. In further embodiments, at least one R₂₀ isOCH₂-phenyl.

(12i) In some embodiments of Formula (I), at least one R₂₀ is(CH₂)₀₋₃-heterocyclyl which comprises a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the heterocyclyl isselected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl,triazolidinyl, oxazolidinyl, isoxazolidinyl, oxadiazolidinyl,dioxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl,dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.,and is optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), and C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl). In other embodiments, at least one R₂₀ is(CH₂)₀₋₁-heterocycle optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl (e.g., methyl,ethyl, propyl, i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, propoxy, or butoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, orCF₃), (C₁-C₄) haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g.,F, Cl, Br or I), and C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl). In other embodiments, at leastone R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl, pyrrolidinyl, morpholinyl,or piperazinyl wherein the pyrrolidinyl, morpholinyl, and piperazinylare each optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), and C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl). In other embodiments, at least one R₂₀ isCH₂-pyrrolidinyl, CH₂-piperazinyl, pyrrolidinyl, morpholinyl, orpiperazinyl, wherein the pyrrolidinyl, morpholinyl, and piperazinyl areeach optionally substituted with one or more (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl), or C(O)O(C₁-C₄)alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl). In otherembodiments, at least one R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl,morpholinyl, or piperazinyl, wherein the pyrrolidinyl, morpholinyl, andpiperazinyl are optionally methyl, ethyl, or C(O)O-t-butyl.

(13a) In some embodiments of Formula (I), R₂₁ is H.

(13b) In some embodiments of Formula (I), R₂₁ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂₁ ismethyl. In other embodiments, R₂₁ is ethyl.

(14a) In some embodiments of Formula (I), R₂₂ is H.

(14b) In some embodiments of Formula (I), R₂₂ is (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl) optionally substituted withone or more substituents independently selected from NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, triazolidinyl, oxazolidinyl,isoxazolidinyl, oxadiazolidinyl, dioxazolidinyl, thiazolidinyl,isothiazolidinyl, thiadiazolidinyl, dithiazolidinyl, piperidinyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, dioxanyl,etc.). In other embodiments, R₂₂ is (C₁-C₄) alkyl (e.g., methyl, ethyl,propyl, i-propyl, or butyl) optionally substituted with one to twosubstituents independently selected from NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄)alkyl)₂, and 6-membered heterocycle comprising 1-3 heteroatoms selectedfrom N, O, and S. In further embodiments, R₂₂ is ethyl, propyl, or butyloptionally substituted with dimethylamino, diethylamino, or morpholinyl.

(14c) In some embodiments of Formula (I), R₂₁ and R₂₂ together with thenitrogen atom to which they are attached form a 5-membered heterocyclyloptionally containing 1-2 additional heteroatoms selected from N, O, andS. In other embodiments, R₂₁ and R₂₂ together with the nitrogen atom towhich they are attached form a 6-membered heterocycle optionallycontaining 1-2 additional heteroatoms selected from N, O, and S. Infurther embodiments, R₂₁ and R₂₂ together with the nitrogen atom towhich they are attached form a morpholinyl.

(15a) In some embodiments of Formula (I), R₁ is (C₆-C₁₀) aryl optionallysubstituted with one or more R₁₁. In other embodiments, R₁ is phenyloptionally substituted with one or more R₁₁.

(15b) In some embodiments of Formula (I), R₁ is heteroaryl comprisingone or two 5- to 7-membered rings and 1-4 heteroatoms selected from N,O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl,isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl, isothiazolyl,thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl, pyridazinyl,pyrimidinyl, triazinyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl,quinolinyl, thiazolopyridinyl, pyrazolopyrimidinyl, etc.) optionallysubstituted with one or more R₁₁. In other embodiments, R₁ is heteroarylcomprising a 5-membered ring and 1-3 heteroatoms selected from N, O, andS, optionally substituted with one or more R₁₁. In other embodiments, R₁is heteroaryl comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, optionally substituted with one or more R₁₁. In otherembodiments, R₁ is heteroaryl comprising a 5-membered ring fused with a6-membered ring and 1-4 heteroatoms selected from N, O, and S,optionally substituted with one or more R₁₁. In other embodiments, R₁ isselected from:

wherein each moiety is optionally substituted with one or more R₁₁. Inother embodiments, R₁ is selected from:

wherein each moiety is optionally substituted with one or more R₁₁. Inother embodiments, R₁ is

(16a) In some embodiments of Formula (I), at least one R₁₁ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl) optionallysubstituted with one or more R₁₂. In other embodiments, at least one R₁₁is methyl. In other embodiments, at least one R₁₁ is propyl optionallysubstituted with one to two R₁₂.

(16b) In some embodiments of Formula (I), at least one R₁₁ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃). In further embodiments, at least one R₁₁ is CF₃.

(16c) In some embodiments of Formula (I), at least one R₁₁ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(16d) In some embodiments of Formula (I), at least one R₁₁ is halogen(e.g., F, Cl, Br or I). In other embodiments, at least one R₁₁ is F. Inother embodiments, at least one R₁₁ is Cl. In other embodiments, atleast one R₁₁ is Br.

(16e) In some embodiments of Formula (I), at least one R₁₁ is NO₂, OH,or CN.

(16f) In some embodiments of Formula (I), at least one R₁₁ is C(O)R₁₃ orC(O)OR₁₃. In other embodiments, at least one R₁₁ is C(O)OCH₂CH₃.

(16g) In some embodiments of Formula (I), at least one R₁₁ isC(O)NR₁₃R₁₄ or NR₁₃R₁₄. In other embodiments, at least one R₁₁ isC(O)NR₁₃R₁₄ or NH₂.

(16h) In some embodiments of Formula (I), at least one R₁₁ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl) optionally substituted with one or more R₁₂. In furtherembodiments, at least one R₁₁ is cyclopropyl.

(16i) In some embodiments of Formula (I), at least one R₁₁ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)optionally substituted with one or more R₁₂.

(16j) In some embodiments of Formula (I), at least one R₁₁ is (C₆-C₁₀)aryl optionally substituted with one or more R₁₂. In furtherembodiments, at least one R₁₁ is phenyl optionally substituted with oneor more R₁₂.

(16k) In some embodiments of Formula (I), at least one R₁₁ is heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl,isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl,pyridazinyl, pyrimidinyl, triazinyl, benzothiazolyl, benzoimidazolyl,benzooxazolyl, quinolinyl, etc.) comprising 1-3 heteroatoms selectedfrom N, O, and S, optionally substituted with one or more R₁₂. In otherembodiments, at least one R₁₁ is heteroaryl comprising a 6-membered ring(e.g., pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, etc.) optionallysubstituted with one or more R₁₂. In other embodiments, at least one R₁₁is pyridinyl optionally substituted with one or more R₁₂. In furtherembodiments, at least one R₁₁ is pyridinyl.

(17a) In some embodiments of Formula (I), at least one R₁₂ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl).

(17b) In some embodiments of Formula (I), at least one R₁₂ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃).

(17c) In some embodiments of Formula (I), at least one R₁₂ is (C₁-C₄)alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(17d) In some embodiments of Formula (I), at least one R₁₂ is halogen(e.g., F, Cl, Br or I).

(17e) In some embodiments of Formula (I), at least one R₁₂ is NO₂, OH,or CN.

(17f) In some embodiments of Formula (I), at least one R₁₂ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl).

(17g) In some embodiments of Formula (I), at least one R₁₂ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)comprising 1-3 heteroatoms selected from N, O, and S. In otherembodiments, at least one R₁₂ is piperidinyl, piperazinyl, ormorpholinyl. In further embodiments, at least one R₁₂ is morpholinyl.

(17h) In some embodiments of Formula (I), at least one R₁₂ is (C₆-C₁₀)aryl optionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, orbutyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy),(C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄) haloalkoxy (e.g.,OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br or I), NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), (C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl), and heterocyclyl comprising a5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S(e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl,oxazolidinyl, isoxazolidinyl, oxadiazolidinyl, dioxazolidinyl,thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, dithiazolidinyl,piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl,dioxanyl, azepinyl, diazepinyl, etc.).

(17i) In some embodiments of Formula (I), R₁₂ is heteroaryl comprisingone or two 5- to 7-membered rings and 1-4 heteroatoms selected from N,O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl,isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl, isothiazolyl,thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl, pyridazinyl,pyrimidinyl, triazinyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl,quinolinyl, etc.) optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), (C₃-C₇) cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl), and heterocyclylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,triazolidinyl, oxazolidinyl, isoxazolidinyl, oxadiazolidinyl,dioxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl,dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl,etc.). In other embodiments, at least one R₁₂ is heteroaryl comprising a5-membered ring fused with a 6-membered ring and 1-4 heteroatomsselected from N, O, and S, optionally substituted with one or moresubstituents independently selected from NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), and(C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl).

(18a) In some embodiments of Formula (I), at least one R₁₃ is H.

(18b) In some embodiments of Formula (I), at least one R₁₃ is (C₁-C₄)alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl) optionallysubstituted with one or more substituents independently selected fromhalogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), andheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl,etc.). In other embodiments, at least one R₁₃ is methyl, ethyl, orpropyl. In other embodiments, at least one R₁₃ is ethyl, propyl, orbutyl, wherein the ethyl, propyl, and butyl are optionally substitutedwith one to two substituents independently selected from NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocycle comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S. In other embodiments, atleast one R₁₃ is ethyl, propyl, or butyl, wherein the ethyl, propyl, andbutyl are optionally substituted with one to two substituentsindependently selected from N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino) and heterocycle comprisinga 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S.In other embodiments, at least one R₁₃ is ethyl, propyl, or butyl,wherein the ethyl, propyl, and butyl are optionally substituted with oneto two substituents independently selected from dimethylamino andheterocycle comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S. In other embodiments, at least one R₁₃ is ethyl,propyl, or butyl wherein the ethyl, propyl, and butyl are optionallysubstituted with one to two substituents independently selected fromdimethylamino, morpholinyl, piperidinyl or piperazinyl. In furtherembodiments, at least one R₁₃ is ethyl, propyl, or butyl wherein theethyl, propyl, and butyl are optionally substituted with dimethylaminoor morpholinyl.

(18c) In some embodiments of Formula (I), at least one R₁₃ is (C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl).

(18d) In some embodiments of Formula (I), at least one R₁₃ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)optionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, orbutyl), halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), andheterocycle comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S. In other embodiments, at least one R₁₃ isheterocycle comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocycle comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S. In other embodiments, atleast one R₁₃ is morpholinyl, piperidinyl, or piperazinyl, wherein themorpholinyl, piperidinyl, and piperazinyl are optionally substitutedwith one or more substituents independently selected from (C₁-C₄) alkyl(e.g., methyl, ethyl, propyl, i-propyl, or butyl), halogen (e.g., F, Cl,Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino,propylamino, or butylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), and heterocyclecomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S. In other embodiments, at least one R₁₃ is morpholinyl,piperidinyl, or piperazinyl, wherein the morpholinyl, piperidinyl, andpiperazinyl are optionally substituted with (C₁-C₄) alkyl (e.g., methyl,ethyl, propyl, i-propyl, or butyl), halogen (e.g., F, Cl, Br or I), OH,NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), or heterocycle comprising a 5- to7-membered ring and 1-3 heteroatoms selected from N, O, and S. In otherembodiments, at least one R₁₃ is morpholinyl, piperidinyl, orpiperazinyl, wherein the morpholinyl, piperidinyl, and piperazinyl areoptionally substituted with (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), or heterocycle comprisinga 6-membered ring and 1-3 heteroatoms selected from N, O, and S. Infurther embodiments, at least one R₁₃ is morpholinyl, piperidinyl, orpiperazinyl, wherein the morpholinyl, piperidinyl, and piperazinyl areoptionally substituted with methyl, dimethylamino, or morpholinyl.

(19a) In some embodiments of Formula (I), at least one R₁₄ is H.

(19b) In some embodiments of Formula (I), at least one R₁₄ is (C₁-C₃)alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

(20a) In some embodiments of Formula (I), m is 0 or 1.

(20b) In some embodiments of Formula (I), m is 0.

(20c) In some embodiments of Formula (I), m is 1.

(21a) In some embodiments of Formula (I), n is 0 or 1.

(21b) In some embodiments of Formula (I), n is 0.

(21c) In some embodiments of Formula (I), n is 1.

(22a) In some embodiments of Formula (I), p is 0, 1, 2, 3, or 4. Inother embodiments, p is 0, 1, 2, or 3. In other embodiments, p is 0, 1,or 2.

(22b) In some embodiments of Formula (I), p is 0 or 1.

(22c) In some embodiments of Formula (I), p is 1 or 2. In otherembodiments, p is 2 or 3.

(22d) In some embodiments of Formula (I), p is 0. In other embodiments,p is 1. In other embodiments, p is 2. In other embodiments, p is 3. Inother embodiments, p is 4.

In some embodiments of Formula (I), R₅ is

wherein q is 0, 1, 2, 3, or 4.

In some embodiments of Formula (I), each of the substituents defined forany one of X₁, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, m, n, p, and q can be combined with any of thesubstituents defined for the remainder of X₁, R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, m, n, p, andq.

(23) In some embodiments, R₁ is as defined in (15a).

(24) In some embodiments, R₁ is as defined in (15a) and m is as definedin (20b).

(25) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), and R₂ is as defined in (1a).

(26) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21b).

(27) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3a).

(28) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(29) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3b).

(30) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(31) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(32) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR % is as defined in (5a).

(33) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21c).

(34) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3a).

(35) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(36) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3b).

(37) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(38) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(39) In some embodiments, R₁ is as defined in (15a), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR % is as defined in (5a).

(40) In some embodiments, R₁ is as defined in (15a) and m is as definedin (20c).

(41) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), and R₂ is as defined in (1a).

(42) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), and R₃ is as defined in (2a).

(43) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21b).

(44) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3a).

(45) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(46) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3b).

(47) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(48) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(49) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

(50) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21c).

(51) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3a).

(52) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(53) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3b).

(54) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(55) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(56) In some embodiments, R₁ is as defined in (15a), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

(57) In some embodiments, R₁ is as defined in (15b).

(58) In some embodiments, R₁ is as defined in (15b) and m is as definedin (20b).

(59) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), and R₂ is as defined in (1a).

(60) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21b).

(61) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3a).

(62) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(63) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), and R₄ is asdefined in (3b).

(64) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(65) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(66) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21b), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR₆ is as defined in (5a).

(67) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), and n is as defined in (21c).

(68) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3a).

(69) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3a), and R₅ is as defined in (7a).

(70) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), and R₄ is asdefined in (3b).

(71) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), and R₅ is as defined in (7a).

(72) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), and X₁ is as defined in (4b).

(73) In some embodiments, R₁ is as defined in (15b), m is as defined in(20b), R₂ is as defined in (1a), n is as defined in (21c), R₄ is asdefined in (3b), R₅ is as defined in (7a), X₁ is as defined in (4b), andR₆ is as defined in (5a).

(74) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c).

(75) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), and R₂ is as defined in (1a).

(76) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), and R₃ is as defined in (2a).

(77) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21b).

(78) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3a).

(79) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(80) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), and R₄ is as defined in (3b).

(81) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(82) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(83) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21b), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

(84) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), and n is asdefined in (21c).

(85) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3a).

(86) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3a), and R₅ is as defined in(7a).

(87) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), and R₄ is as defined in (3b).

(88) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), and R₅ is as defined in(7a).

(89) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a),and X₁ is as defined in (4b).

(90) In some embodiments, R₁ is as defined in (15b), m is as defined in(20c), R₂ is as defined in (1a), R₃ is as defined in (2a), n is asdefined in (21c), R₄ is as defined in (3b), R₅ is as defined in (7a), X₁is as defined in (4b), and R₆ is as defined in (5a).

In other embodiments, the compounds of Formula (I′) have the structureof Formula (Ia) or (Ib):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein:

R₁ is (C₆-C₁₀) aryl, or heteroaryl comprising one or two 5- to7-membered rings and 1-4 heteroatoms selected from N, O, and S, whereinthe aryl and heteroaryl are each optionally substituted with one or moreR₁₁;

each R₁₁ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, OH, CN,C(O)R₁₃, C(O)OR₁₃, C(O)NR₁₃R₁₄, NR₁₃R₁₄, (C₃-C₇) cycloalkyl,heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, (C₆-C₁₀) aryl, and heteroaryl comprising oneor two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O,and S, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroarylare each optionally substituted with one or more R₁₂;

each R₁₂ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, OH, CN,(C₃-C₇) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S, (C₆-C₁₀) aryl, and heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the aryl and heteroaryl are eachoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, (C₃-C₇)cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S;

each R₁₃ is independently selected from H, (C₁-C₄) alkyl, (C₃-C₇)cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl,and heterocyclyl are each optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl, halogen, OH,NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, and heterocyclyl comprising a5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;

each R₁₄ is independently H or (C₁-C₃) alkyl;

R₂ is H or (C₁-C₃) alkyl;

R₃ is H or (C₁-C₃) alkyl;

R₄ is (C₁-C₃) alkyl or

X₁ is N or CR₆;

R₆ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkoxy, halogen, NO₂, NH₂, OH, or CN;

each R₇ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, NH₂, OH, and CN;

each R₁₉ is independently selected from halogen, (C₃-C₇) cycloalkyl,(C₄-C₇) cycloalkenyl, (C₆-C₁₀) aryl, NH—(C₆-C₁₀) aryl, and heteroarylcomprising one or two 5- to 7-membered ring and 1-4 heteroatoms selectedfrom N, O, and S, wherein the aryl and heteroaryl are each optionallysubstituted with one or more R₂₀;

each R₂₀ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(O)OH, C(O)O(C₁-C₄)alkyl, C(O)NR₂₁R₂₂, NH₂, OH, CN, O(CH₂)₀₋₃—(C₆-C₁₀) aryl, and(CH₂)₀₋₃-heterocyclyl which comprises a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, and C(O)O(C₁-C₄) alkyl);

R₂₁ is H or (C₁-C₃) alkyl;

R₂₂ is H or (C₁-C₄) alkyl optionally substituted with one or moresubstituents independently selected from NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄)alkyl)₂, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S; or

R₂₁ and R₂₂ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl optionally containing 1-2additional heteroatoms selected from N, O, and S;

m and n are each independently 0 or 1; and

p and q are each independently 0, 1, 2, 3 or 4;

provided that when m is 0, n is 0, p is 0, R₁₅ and R₁₆ together with thenitrogen atom to which they are attached form an unsubstitutedisoindolinone, and R₆ is H, then R₁ is not

and

provided that R₄ is not 4-fluoro-2-hydroxyphenyl.

(101a) In some embodiments of Formula (Ia) or (Ib), R₂ is H.

(101b) In some embodiments of Formula (Ia) or (Ib), R₂ is (C₁-C₃) alkyl(e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂ ismethyl. In other embodiments, R₂ is ethyl.

(102a) In some embodiments of Formula (Ia) or (Ib), R₃ is H.

(102b) In some embodiments of Formula (Ia) or (Ib), R₃ is (C₁-C₃) alkyl(e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments, R₃ ismethyl. In other embodiments, R₃ is ethyl.

(103a) In some embodiments of Formula (Ia) or (Ib), R₄ is (C₁-C₃) alkyl(e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments, R₄ ismethyl. In other embodiments, R₄ is ethyl.

(103b) In some embodiments of Formula (Ia) or (Ib), R₄ is

(e.g., phenyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl).

(104a) In some embodiments of Formula (Ia) or (Ib), X₁ is N.

(104b) In some embodiments of Formula (Ia) or (Ib), X₁ is CR₆.

(105a) In some embodiments of Formula (Ia) or (Ib), R₆ is H.

(105b) In some embodiments of Formula (Ia) or (Ib), R₆ is (C₁-C₄) alkyl(e.g., methyl, ethyl, propyl, i-propyl, or butyl).

(105c) In some embodiments of Formula (Ia) or (Ib), R₆ is (C₁-C₄)haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy (e.g., OCH₂F,OCHF₂, or OCF₃).

(105d) In some embodiments of Formula (Ia) or (Ib), R₆ is (C₁-C₄) alkoxy(e.g., methoxy, ethoxy, propoxy, or butoxy).

(105e) In some embodiments of Formula (Ia) or (Ib), R₆ is halogen (e.g.,F, Cl, Br or I). In other embodiments, R₆ is F or Cl. In furtherembodiments, R₆ is F.

(105f) In some embodiments of Formula (Ia) or (Ib), R₆ is NO₂, NH₂, OH,or CN. In further embodiments, R₆ is NO₂ or NH₂.

(106a) In some embodiments of Formula (Ia) or (Ib), at least one R₇ is(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl).

(106b) In some embodiments of Formula (Ia) or (Ib), at least one R₇ is(C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy(e.g., OCH₂F, OCHF₂, or OCF₃).

(106c) In some embodiments of Formula (Ia) or (Ib), at least one R₇ is(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(106d) In some embodiments of Formula (Ia) or (Ib), at least one R₇ ishalogen (e.g., F, Cl, Br or I). In other embodiments, at least one R₇ isF or Cl. In further embodiments, at least one R₇ is F.

(106e) In some embodiments of Formula (Ia) or (Ib), at least one R₇ isNO₂, NH₂, OH, or CN. In further embodiments, at least one R₇ is NO₂ orNH₂.

(106f) In some embodiments of Formula (Ia) or (Ib), at least one R₇ ishalogen (e.g., F, Cl, Br or I) and at least one R₇ is OH.

(106g) In some embodiments of Formula (Ia) or (Ib), one R₇ is halogen(e.g., F, Cl, Br or I) and one R₇ is OH.

(111a) In some embodiments of Formula (Ia) or (Ib), at least one R₁₉ ishalogen (e.g., F, Cl, Br or I). In other embodiments, at least one R₁₉is F, Cl, or Br. In other embodiments, at least one R₁₉ is F. In otherembodiments, at least one R₁₉ is Cl. In other embodiments, at least oneR₁₉ is Br.

(111b) In some embodiments of Formula (Ia) or (Ib), at least one R₁₉ is(C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl).

(111c) In some embodiments of Formula (Ia) or (Ib), at least one R₁₉ is(C₄-C₇) cycloalkenyl (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl,or cycloheptenyl). In other embodiments, at least one R₁₉ iscyclohexenyl.

(111d) In some embodiments of Formula (Ia) or (Ib), at least one R₁₉ is(C₆-C₁₀) aryl optionally substituted with one or more R₂₀. In otherembodiments, at least one R₁₉ is phenyl optionally substituted with oneor more R₂₀. In other embodiments, at least one R₁₉ is phenyl optionallysubstituted with one to three R₂₀. In other embodiments, at least oneR₁₉ is phenyl.

(111e) In some embodiments of Formula (Ia) or (Ib), at least one R₁₉ isNH—(C₆-C₁₀) aryl optionally substituted with one or more R₂₀. In otherembodiments, at least one R₁₉ is NH-phenyl optionally substituted withone or more R₂₀. In other embodiments, at least one R₁₉ is NH-phenyloptionally substituted with one to three R₂₀. In other embodiments, atleast one R₁₉ is NH-phenyl.

(111f) In some embodiments of Formula (Ia) or (Ib), at least one R₁₉ isheteroaryl comprising one or two 5- to 7-membered rings and 1-4heteroatoms selected from N, O, and S (e.g., pyrrolyl, pyrazolyl,imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl,pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, quinolinyl,isoquinolinyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl,thiazolopyridinyl, pyrazolopyrimidinyl, etc.) optionally substitutedwith one or more R₂₀. In other embodiments, at least one R₁₉ ispyrazolyl, thiophenyl, pyridinyl, pyrimidinyl, indolyl, or quinolinyloptionally substituted with one or more R₂₀.

(112a) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ is(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl). Infurther embodiments, at least one R₂₀ is methyl or ethyl.

(112b) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ is(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy). In furtherembodiments, at least one R₂₀ is methoxy.

(112c) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ is(C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy(e.g., OCH₂F, OCHF₂, or OCF₃). In further embodiments, at least one R₂₀is CF₃ or OCF₃.

(112d) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ ishalogen (e.g., F, Cl, Br or I). In further embodiments, at least one R₂₀is F.

(112e) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ isC(O)OH or C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, orbutyl). In further embodiments, at least one R₂₀ is C(O)OH or C(O)OCH₃.

(112f) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ isNH₂, OH, or CN.

(112g) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ isC(O)NR₂₁R₂₂.

(112h) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ isO(CH₂)₀₋₃—(C₆-C₁₀) aryl. In further embodiments, at least one R₂₀ isOCH₂-phenyl.

(112i) In some embodiments of Formula (Ia) or (Ib), at least one R₂₀ is(CH₂)₀₋₃-heterocyclyl which comprises a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the heterocyclyl isselected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl,triazolidinyl, oxazolidinyl, isoxazolidinyl, oxadiazolidinyl,dioxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl,dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.,and is optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), and C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl). In other embodiments, at least one R₂₀ is(CH₂)₀₋₁-heterocycle optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl (e.g., methyl,ethyl, propyl, i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, propoxy, or butoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, orCF₃), (C₁-C₄) haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g.,F, Cl, Br or I), and C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, butyl, i-butyl, or t-butyl). In other embodiments, at leastone R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl, pyrrolidinyl, morpholinyl,or piperazinyl wherein the pyrrolidinyl, morpholinyl, and piperazinylare each optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), and C(O)O(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl,butyl, i-butyl, or t-butyl). In other embodiments, at least one R₂₀ isCH₂-pyrrolidinyl, CH₂-piperazinyl, pyrrolidinyl, morpholinyl, orpiperazinyl, wherein the pyrrolidinyl, morpholinyl, and piperazinyl areeach optionally substituted with one or more (C₁-C₄) alkyl (e.g.,methyl, ethyl, propyl, i-propyl, or butyl), or C(O)O(C₁-C₄)alkyl (e.g.,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl). In otherembodiments, at least one R₂₀ is CH₂-pyrrolidinyl, CH₂-piperazinyl,morpholinyl, or piperazinyl, wherein the pyrrolidinyl, morpholinyl, andpiperazinyl are optionally methyl, ethyl, or C(O)O-t-butyl.

(113a) In some embodiments of Formula (Ia) or (Ib), R₂₁ is H.

(113b) In some embodiments of Formula (Ia) or (Ib), R₂₁ is (C₁-C₃) alkyl(e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂₁ ismethyl. In other embodiments, R₂₁ is ethyl.

(114a) In some embodiments of Formula (Ia) or (Ib), R₂₂ is H.

(114b) In some embodiments of Formula (Ia) or (Ib), R₂₂ is (C₁-C₄) alkyl(e.g., methyl, ethyl, propyl, i-propyl, or butyl) optionally substitutedwith one or more substituents independently selected from NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, triazolidinyl, oxazolidinyl,isoxazolidinyl, oxadiazolidinyl, dioxazolidinyl, thiazolidinyl,isothiazolidinyl, thiadiazolidinyl, dithiazolidinyl, piperidinyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, dioxanyl,etc.). In other embodiments, R₂₂ is (C₁-C₄) alkyl (e.g., methyl, ethyl,propyl, i-propyl, or butyl) optionally substituted with one to twosubstituents independently selected from NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄)alkyl)₂, and 6-membered heterocycle comprising 1-3 heteroatoms selectedfrom N, O, and S. In further embodiments, R₂₂ is ethyl, propyl, or butyloptionally substituted with dimethylamino, diethylamino, or morpholinyl.

(114c) In some embodiments of Formula (Ia) or (Ib), R₂₁ and R₂₂ togetherwith the nitrogen atom to which they are attached form a 5-memberedheterocyclyl optionally containing 1-2 additional heteroatoms selectedfrom N, O, and S. In other embodiments, R₂₁ and R₂₂ together with thenitrogen atom to which they are attached form a 6-membered heterocycleoptionally containing 1-2 additional heteroatoms selected from N, O, andS. In further embodiments, R₂₁ and R₂₂ together with the nitrogen atomto which they are attached form a morpholinyl.

(115a) In some embodiments of Formula (Ia) or (Ib), R₁ is (C₆-C₁₀) aryloptionally substituted with one or more R₁₁. In other embodiments, R₁ isphenyl optionally substituted with one or more R₁₁.

(115b) In some embodiments of Formula (Ia) or (Ib), R₁ is heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl,isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl,pyridazinyl, pyrimidinyl, triazinyl, benzothiazolyl, benzoimidazolyl,benzooxazolyl, quinolinyl, thiazolopyridinyl, pyrazolopyrimidinyl, etc.)optionally substituted with one or more R₁₁. In other embodiments, R₁ isheteroaryl comprising a 5-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, optionally substituted with one or more R₁₁. In otherembodiments, R₁ is heteroaryl comprising a 6-membered ring and 1-3heteroatoms selected from N, O, and S, optionally substituted with oneor more R₁₁. In other embodiments, R₁ is heteroaryl comprising a5-membered ring fused with a 6-membered ring and 1-4 heteroatomsselected from N, O, and S, optionally substituted with one or more R₁₁.In other embodiments, R₁ is selected from:

wherein each moiety is optionally substituted with one or more R₁₁. Inother embodiments, R₁ is selected from:

wherein each moiety is optionally substituted with one or more R₁₁. Inother embodiments, R₁ is

(116a) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ is(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl)optionally substituted with one or more R₁₂. In other embodiments, atleast one R₁₁ is methyl. In other embodiments, at least one R₁₁ ispropyl optionally substituted with one to two R₁₂.

(116b) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ is(C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy(e.g., OCH₂F, OCHF₂, or OCF₃). In further embodiments, at least one R₁₁is CF₃.

(116c) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ is(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(116d) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ ishalogen (e.g., F, Cl, Br or I). In other embodiments, at least one R₁₁is F. In other embodiments, at least one R₁₁ is Cl. In otherembodiments, at least one R₁₁ is Br.

(116e) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ isNO₂, OH, or CN.

(116f) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ isC(O)R₁₃ or C(O)OR₁₃. In other embodiments, at least one R₁₁ isC(O)OCH₂CH₃.

(116g) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ isC(O)NR₁₃R₁₄ or NR₁₃R₁₄. In other embodiments, at least one R₁₁ isC(O)NR₁₃R₁₄ or NH₂.

(116h) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ is(C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl) optionally substituted with one or more R₁₂.In further embodiments, at least one R₁₁ is cyclopropyl.

(116i) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)optionally substituted with one or more R₁₂.

(116j) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ is(C₆-C₁₀) aryl optionally substituted with one or more R₁₂. In furtherembodiments, at least one R₁₁ is phenyl optionally substituted with oneor more R₁₂.

(116k) In some embodiments of Formula (Ia) or (Ib), at least one R₁₁ isheteroaryl comprising one or two 5- to 7-membered rings and 1-4heteroatoms selected from N, O, and S (e.g., pyrrolyl, pyrazolyl,imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl,pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, benzothiazolyl,benzoimidazolyl, benzooxazolyl, quinolinyl, etc.) comprising 1-3heteroatoms selected from N, O, and S, optionally substituted with oneor more R₁₂. In other embodiments, at least one R₁₁ is heteroarylcomprising a 6-membered ring (e.g., pyridinyl, pyridazinyl, pyrimidinyl,triazinyl, etc.) optionally substituted with one or more R₁₂. In otherembodiments, at least one R₁₁ is pyridinyl optionally substituted withone or more R₁₂. In further embodiments, at least one R₁₁ is pyridinyl.

(117a) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ is(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl).

(117b) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ is(C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃) or (C₁-C₄) haloalkoxy(e.g., OCH₂F, OCHF₂, or OCF₃).

(117c) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ is(C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy).

(117d) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ ishalogen (e.g., F, Cl, Br or I).

(117e) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ isNO₂, OH, or CN.

(117f) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ is(C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl).

(117g) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)comprising 1-3 heteroatoms selected from N, O, and S. In otherembodiments, at least one R₁₂ is piperidinyl, piperazinyl, ormorpholinyl. In further embodiments, at least one R₁₂ is morpholinyl.

(117h) In some embodiments of Formula (Ia) or (Ib), at least one R₁₂ is(C₆-C₁₀) aryl optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy, ethoxy, propoxy, orbutoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, or CF₃), (C₁-C₄)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g., F, Cl, Br orI), NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), (C₃-C₇) cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl), and heterocyclylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,triazolidinyl, oxazolidinyl, isoxazolidinyl, oxadiazolidinyl,dioxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl,dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl,etc.).

(117i) In some embodiments of Formula (Ia) or (Ib), R₁₂ is heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxazolyl, thiazolyl,isothiazolyl, thiadiazolyl, dithiazolyl, thiophenyl, pyridinyl,pyridazinyl, pyrimidinyl, triazinyl, benzothiazolyl, benzoimidazolyl,benzooxazolyl, quinolinyl, etc.) optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl (e.g., methyl,ethyl, propyl, i-propyl, or butyl), (C₁-C₄) alkoxy (e.g., methoxy,ethoxy, propoxy, or butoxy), (C₁-C₄) haloalkyl (e.g., CH₂F, CHF₂, orCF₃), (C₁-C₄) haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃), halogen (e.g.,F, Cl, Br or I), NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino,propylamino, or butylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), (C₃-C₇) cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl), andheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl,etc.). In other embodiments, at least one R₁₂ is heteroaryl comprising a5-membered ring fused with a 6-membered ring and 1-4 heteroatomsselected from N, O, and S, optionally substituted with one or moresubstituents independently selected from NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), and(C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl).

(118a) In some embodiments of Formula (Ia) or (Ib), at least one R₁₃ isH.

(118b) In some embodiments of Formula (Ia) or (Ib), at least one R₁₃ is(C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, or butyl)optionally substituted with one or more substituents independentlyselected from halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl(e.g., methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄)alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,pyrazolidinyl, imidazolidinyl, triazolidinyl, oxazolidinyl,isoxazolidinyl, oxadiazolidinyl, dioxazolidinyl, thiazolidinyl,isothiazolidinyl, thiadiazolidinyl, dithiazolidinyl, piperidinyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, dioxanyl,azepinyl, diazepinyl, etc.). In other embodiments, at least one R₁₃ ismethyl, ethyl, or propyl. In other embodiments, at least one R₁₃ isethyl, propyl, or butyl, wherein the ethyl, propyl, and butyl areoptionally substituted with one to two substituents independentlyselected from NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino,propylamino, or butylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), and heterocyclecomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S. In other embodiments, at least one R₁₃ is ethyl, propyl, orbutyl, wherein the ethyl, propyl, and butyl are optionally substitutedwith one to two substituents independently selected from N((C₁-C₄)alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino) and heterocycle comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S. In other embodiments, at leastone R₁₃ is ethyl, propyl, or butyl, wherein the ethyl, propyl, and butylare optionally substituted with one to two substituents independentlyselected from dimethylamino and heterocycle comprising a 6-membered ringand 1-3 heteroatoms selected from N, O, and S. In other embodiments, atleast one R₁₃ is ethyl, propyl, or butyl wherein the ethyl, propyl, andbutyl are optionally substituted with one to two substituentsindependently selected from dimethylamino, morpholinyl, piperidinyl orpiperazinyl. In further embodiments, at least one R₁₃ is ethyl, propyl,or butyl wherein the ethyl, propyl, and butyl are optionally substitutedwith dimethylamino or morpholinyl.

(118c) In some embodiments of Formula (Ia) or (Ib), at least one R₁₃ is(C₃-C₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl).

(118d) In some embodiments of Formula (Ia) or (Ib), at least one R₁₃ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,imidazolidinyl, triazolidinyl, oxazolidinyl, isoxazolidinyl,oxadiazolidinyl, dioxazolidinyl, thiazolidinyl, isothiazolidinyl,thiadiazolidinyl, dithiazolidinyl, piperidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, dioxanyl, azepinyl, diazepinyl, etc.)optionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl, i-propyl, orbutyl), halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g.,methylamino, ethylamino, propylamino, or butylamino), N((C₁-C₄) alkyl)₂(e.g., dimethylamino, diethylamino, dipropylamino, or dibutylamino), andheterocycle comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S. In other embodiments, at least one R₁₃ isheterocycle comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, optionally substituted with one or more substituentsindependently selected from (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), halogen (e.g., F, Cl, Br or I), OH, NH₂, NH(C₁-C₄)alkyl (e.g., methylamino, ethylamino, propylamino, or butylamino),N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordibutylamino), and heterocycle comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S. In other embodiments, atleast one R₁₃ is morpholinyl, piperidinyl, or piperazinyl, wherein themorpholinyl, piperidinyl, and piperazinyl are optionally substitutedwith one or more substituents independently selected from (C₁-C₄) alkyl(e.g., methyl, ethyl, propyl, i-propyl, or butyl), halogen (e.g., F, Cl,Br or I), OH, NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino,propylamino, or butylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), and heterocyclecomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S. In other embodiments, at least one R₁₃ is morpholinyl,piperidinyl, or piperazinyl, wherein the morpholinyl, piperidinyl, andpiperazinyl are optionally substituted with (C₁-C₄) alkyl (e.g., methyl,ethyl, propyl, i-propyl, or butyl), halogen (e.g., F, Cl, Br or I), OH,NH₂, NH(C₁-C₄) alkyl (e.g., methylamino, ethylamino, propylamino, orbutylamino), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino, diethylamino,dipropylamino, or dibutylamino), or heterocycle comprising a 5- to7-membered ring and 1-3 heteroatoms selected from N, O, and S. In otherembodiments, at least one R₁₃ is morpholinyl, piperidinyl, orpiperazinyl, wherein the morpholinyl, piperidinyl, and piperazinyl areoptionally substituted with (C₁-C₄) alkyl (e.g., methyl, ethyl, propyl,i-propyl, or butyl), N((C₁-C₄) alkyl)₂ (e.g., dimethylamino,diethylamino, dipropylamino, or dibutylamino), or heterocycle comprisinga 6-membered ring and 1-3 heteroatoms selected from N, O, and S. Infurther embodiments, at least one R₁₃ is morpholinyl, piperidinyl, orpiperazinyl, wherein the morpholinyl, piperidinyl, and piperazinyl areoptionally substituted with methyl, dimethylamino, or morpholinyl.

(119a) In some embodiments of Formula (Ia) or (Ib), at least one R₁₄ isH.

(119b) In some embodiments of Formula (Ia) or (Ib), at least one R₁₄ is(C₁-C₃) alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

(120a) In some embodiments of Formula (Ia) or (Ib), m is 0 or 1.

(120b) In some embodiments of Formula (Ia) or (Ib), m is 0.

(120c) In some embodiments of Formula (Ia) or (Ib), m is 1.

(121a) In some embodiments of Formula (Ia) or (Ib), n is 0 or 1.

(121b) In some embodiments of Formula (Ia) or (Ib), n is 0.

(121c) In some embodiments of Formula (Ia) or (Ib), n is 1.

(122a) In some embodiments of Formula (Ia) or (Ib), p is 0, 1, 2, 3, or4. In other embodiments, p is 0, 1, 2, or 3. In other embodiments, p is0, 1, or 2.

(122b) In some embodiments of Formula (Ia) or (Ib), p is 0 or 1.

(122c) In some embodiments of Formula (Ia) or (Ib), p is 1 or 2. Inother embodiments, p is 2 or 3.

(122d) In some embodiments of Formula (Ia) or (Ib), p is 0. In otherembodiments, p is 1. In other embodiments, p is 2. In other embodiments,p is 3. In other embodiments, p is 4.

(123a) In some embodiments of Formula (Ia) or (Ib), q is 0, 1, 2, 3, or4. In other embodiments, q is 0, 1, 2, or 3. In other embodiments, q is0, 1, or 2.

(123b) In some embodiments of Formula (Ia) or (Ib), q is 0 or 1.

(123c) In some embodiments of Formula (Ia) or (Ib), q is 1 or 2. Inother embodiments, q is 2 or 3.

(123d) In some embodiments of Formula (Ia) or (Ib), q is 0. In otherembodiments, q is 1. In other embodiments, q is 2. In other embodiments,q is 3. In other embodiments, q is 4.

(123e) In some embodiments of Formula (Ia) or (Ib), q is 0.

In some embodiments of Formula (Ia) or (Ib), each of the substituentsdefined for any one of X₁, R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, R₁₂, R₁₃, R₁₄,R₁₉, R₂₀, R₂₁, R₂₂, m, n, p, and q can be combined with any of thesubstituents defined for the remainder of X₁, R₁, R₂, R₃, R₄, R₆, R₇,R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, m, n, p, and q.

(130) In some embodiments, R₁ is as defined in (115a).

(131) In some embodiments, R₁ is as defined in (115a) and m is asdefined in (120b).

(132) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), and R₂ is as defined in (101a).

(133) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), and n is as defined in (121b).

(134) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), and R₄is as defined in (103a).

(135) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), and R₄is as defined in (103b).

(136) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), R₄ isas defined in (103b), and X₁ is as defined in (104b).

(137) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), R₄ isas defined in (103b), X₁ is as defined in (104b), and R₆ is as definedin (105a).

(138) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), and n is as defined in (121c).

(139) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), and R₄is as defined in (103a).

(140) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), and R₄is as defined in (103b).

(141) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), R₄ isas defined in (103b), and X₁ is as defined in (104b).

(142) In some embodiments, R₁ is as defined in (115a), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), R₄ isas defined in (103b), X₁ is as defined in (104b), and R₆ is as definedin (105a).

(143) In some embodiments, R₁ is as defined in (115a) and m is asdefined in (120c).

(144) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), and R₂ is as defined in (101a).

(145) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), and R₃ is as defined in (102a).

(146) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), and nis as defined in (121b).

(147) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), and R₄ is as defined in (103a).

(148) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), and R₄ is as defined in (103b).

(149) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), R₄ is as defined in (103b), and X₁ is as definedin (104b).

(150) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), R₄ is as defined in (103b), X₁ is as defined in(104b), and R₆ is as defined in (105a).

(151) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), and nis as defined in (121c).

(152) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), and R₄ is as defined in (103a).

(153) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), and R₄ is as defined in (103b).

(154) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), R₄ is as defined in (103b), and X₁ is as definedin (104b).

(155) In some embodiments, R₁ is as defined in (115a), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), R₄ is as defined in (103b), X₁ is as defined in(104b), and R₆ is as defined in (105a).

(156) In some embodiments, R₁ is as defined in (115b).

(157) In some embodiments, R₁ is as defined in (115b) and m is asdefined in (120b).

(158) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), and R₂ is as defined in (101a).

(159) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), and n is as defined in (121b).

(160) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), and R₄is as defined in (103a).

(161) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), and R₄is as defined in (103b).

(162) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), R₄ isas defined in (103b), and X₁ is as defined in (104b).

(163) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121b), R₄ isas defined in (103b), X₁ is as defined in (104b), and R₆ is as definedin (105a).

(164) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), and n is as defined in (121c).

(165) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), and R₄is as defined in (103a).

(166) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), and R₄is as defined in (103b).

(167) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), R₄ isas defined in (103b), and X₁ is as defined in (104b).

(168) In some embodiments, R₁ is as defined in (115b), m is as definedin (120b), R₂ is as defined in (101a), n is as defined in (121c), R₄ isas defined in (103b), X₁ is as defined in (104b), and R₆ is as definedin (105a).

(169) In some embodiments, R₁ is as defined in (115b) and m is asdefined in (120c).

(170) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), and R₂ is as defined in (101a).

(171) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), and R₃ is as defined in (102a).

(172) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), and nis as defined in (121b).

(173) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), and R₄ is as defined in (103a).

(174) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), and R₄ is as defined in (103b).

(175) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), R₄ is as defined in (103b), and X₁ is as definedin (104b).

(176) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121b), R₄ is as defined in (103b), X₁ is as defined in(104b), and R₆ is as defined in (105a).

(177) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), and nis as defined in (121c).

(178) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), and R₄ is as defined in (103a).

(179) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), and R₄ is as defined in (103b).

(180) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), R₄ is as defined in (103b), and X₁ is as definedin (104b).

(181) In some embodiments, R₁ is as defined in (115b), m is as definedin (120c), R₂ is as defined in (101a), R₃ is as defined in (102a), n isas defined in (121c), R₄ is as defined in (103b), X₁ is as defined in(104b), and R₆ is as defined in (105a).

(182) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (130)-(181), and q is as defined in (123b).

(183) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (130)-(181), and q is as defined in (123e).

(184) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (134)-(137), and q is as defined in (123b).

(185) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (134)-(137), and q is as defined in (123e).

(186) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (139)-(142), and q is as defined in (123b).

(187) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (139)-(142), and q is as defined in (123e).

(188) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (137) or (142), and q is as defined in (123b).

(189) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (137) or (142), and q is as defined in (123e).

(190) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (147)-(150), and q is as defined in (123b).

(191) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (147)-(150), and q is as defined in (123e).

(192) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (152)-(155), and q is as defined in (123b).

(193) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (152)-(155), and q is as defined in (123e).

(194) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (150) or (155), and q is as defined in (123b).

(195) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (150) or (155), and q is as defined in (123e).

(196) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (160)-(163), and q is as defined in (123b).

(197) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (160)-(163), and q is as defined in (123e).

(198) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (165)-(168), and q is as defined in (123b).

(199) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (165)-(168), and q is as defined in (123e).

(200) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (163) or (168), and q is as defined in (123b).

(201) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (163) or (168), and q is as defined in (123e).

(202) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (173)-(176), and q is as defined in (123b).

(203) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (173)-(176), and q is as defined in (123e).

(204) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (178)-(181), and q is as defined in (123b).

(205) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in any of (178)-(181), and q is as defined in (123e).

(206) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (176) or (181), and q is as defined in (123b).

(207) In some embodiments, R₁, R₂, R₃, R₄, R₆, X₁, m, and/or n are asdefined in (176) or (181), and q is as defined in (123e).

Non-limiting illustrative compounds of the disclosure include:

Com- pound Num- ber Structure Compound Name I-1

(S)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-((R)-1- phenylethyl)acetamideI-2

(S)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-((S)-1- phenylethyl)acetamideI-3

ethyl (S)-2-(2- (1-oxoisoindolin-2- yl)-3-phenylpropanamido)thiazole-4-carboxylate I-4

ethyl (R)-2-(2- (1-oxoisoindolin-2- yl)-2-phenylacetamido)thiazole-4-carboxylate I-5

(R)-N-(4- methylthiazol-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-6

(R)-2-(1-oxoisoindolin-2-yl)- 2-phenyl-N-(4- (trifluoromethyl)thiazol-2-yl)acetamide I-7

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(pyridin-3-yl) acetamide I-8

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(pyridin-4-yl) acetamide I-9

(R)-N-methyl-2- (2-(1-oxoisoindolin- 2-yl)-2-phenylacetamido)thiazole-4-carboxamide I-10

(R)-N-(2- morpholinoethyl)-2-(2-(1- oxoisoindolin-2-yl)-2-phenylacetamido)thiazole-4- carboxamide I-11

(R)-N-(3- (dimethylamino)propyl)-2- (2-(1-oxoisoindolin-2-yl)-2-phenylacetamido)thiazole-4- carboxamide I-12

(S)-2-(3-nitrophenyl)-2-(1- oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide I-13

(S)-2-(3-aminophenyl)-2-(1- oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide I-14

(R)-N-(3- morpholinopropyl)-2-(2- (1-oxoisoindolin-2-yl)-2-phenylacetamido)thiazole-4- carboxamide I-15

(R)-N-(4- (dimethylamino)butyl)-2- (2-(1-oxoisoindolin-2-yl)-2-phenylacetamido)thiazole-4- carboxamide I-16

(R)-N-(2- (dimethylamino)ethyl)-2- (2-(1-oxoisoindolin-2-yl)-2-phenylacetamido)thiazole-4- carboxamide I-17

(R)-2-(2- (1-oxoisoindolin-2-yl)-2- phenylacetamido)thiazole-4-carboxamide I-18

(R)-2-(3-nitrophenyl)-2-(1- oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide I-19

(R)-N-(oxazol-2-yl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamide I-20

(S)-N-(oxazol-2-yl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamide I-21

(S)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(thiazol-2-yl) acetamide I-22

(R)-N-(4-(morpholine-4- carbonyl)thiazol-2-yl)-2-(1-oxoisoindolin-2-yl)-2- phenylacetamide I-23

(R)-N-(4-(4- (dimethylamino)piperidine-1- carbonyl)thiazol-2-yl)-2-(1-oxoisoindolin-2-yl)-2- phenylacetamide I-24

(R)-N-(4-(4- morpholinopiperidine- 1-carbonyl)thiazol-2-yl)-2-(1-oxoisoindolin-2-yl)-2- phenylacetamide I-25

(R)-N-(4- (4-methylpiperazine-1- carbonyl)thiazol-2-yl)-2-(1-oxoisoindolin-2-yl)-2- phenylacetamide I-26

(R)-N-(3- cyclopropyl-1H-pyrazol-5- yl)-2-(1-oxoisoindolin-2-yl)-2-phenylacetamide I-27

(R)-N-(5- bromopyrazin-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-28

(R)-N-(4- bromopyridin-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-29

(S)-N-(4- bromopyridin-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-30

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(3- (trifluoromethyl)-1H-pyrazol-5-yl)acetamide I-31

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(pyridin-2-yl) acetamide I-32

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(thiazolo [5,4-b]pyridin-2-yl)acetamide I-33

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)acetamide I-34

(R)-N-(1H- imidazol-2-yl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamideI-35

(S)-N-(1H- imidazol-2-yl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamideI-36

(R)-N-(4- bromothiazol-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-37

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(4- (pyridin-4-yl)thiazol-2-yl)acetamide I-38

(R)-2-(3- aminophenyl)-2-(1- oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide I-39

(R)-2-(1- oxoisoindolin-2-yl)-3- phenyl-N-(thiazol-2- yl)propanamideI-40

(R)-N-(5- bromothiazol-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-41

(R)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(1,3,4-thiadiazol-2-yl)acetamide I-42

(S)-2-(1- oxoisoindolin-2-yl)-2- phenyl-N-(1,3,4- thiadiazol-2-yl)acetamide I-43

(R)-N-(4-(3- morpholinopropyl) thiazol-2-yl)-2-(1-oxoisoindolin-2-yl)-2- phenylacetamide I-44

(R)-N-(5-(3- morpholinopropyl) thiazol-2-yl)-2-(1-oxoisoindolin-2-yl)-2- phenylacetamide I-45

(S)-2-(1- oxoisoindolin-2-yl)-3- phenyl-N-(thiazol-2-yl) propanamideI-46

(R)-2-(1-oxo-6-(thiophen- 2-yl)isoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-47

(R)-2-(1-oxo-6-(thiophen- 3-yl)isoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-48

ethyl (S)-2-(2- (1-oxoisoindolin-2- yl)-3-phenylpropanamido)thiazole-4-carboxylate I-49

(S)-N-(5- bromothiazol-2-yl)-2-(1- oxoisoindolin-2-yl)-3-phenylpropanamide I-50

(R)-N-(4- bromothiazol-2-yl)-2-(1- oxoisoindolin-2-yl)-3-phenylpropanamide I-51

(R)-2-(1- oxoisoindolin-2-yl)-N,2- diphenylacetamide I-52

(R)-N-(2- chlorophenyl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamideI-53

(R)-N-(2,5- difluorophenyl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamideI-54

(R)-N-(2,6- dimethylphenyl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamideI-55

(R)-N-(2-fluorophenyl)-2-(1- oxoisoindolin-2-yl)-2- phenylacetamide I-56

(R)-N-(3- fluoropyridin-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-57

(R)-N-(3- chloropyridin-2-yl)-2-(1- oxoisoindolin-2-yl)-2-phenylacetamide I-58

(R)-N-methyl-2- (1-oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-59

(R)-2-(1-oxo- 6-phenylisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-60

(R)-2-(1-oxo-6-(pyridin- 3-yl)isoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-61

(R)-2-(1-oxo-6-(pyridin- 4-yl)isoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-62

(R)-2-(1-oxo-6- (pyrimidin-5- yl)isoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-63

(R)-2-(6-(1-ethyl- 1H-pyrazol-4-yl)- 1-oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-64

(R)-2-(1-oxo- 6-(1H-pyrazol-4- yl)isoindolin-2-yl)- 2-phenyl-N-(thiazol-2-yl)acetamide I-65

(R)-2-(6-(2,3- dihydrobenzo[b] [1,4]dioxin-6-yl)-1- oxoisoindolin-2-yl)-2-phenyl-N- (thiazol-2-yl)acetamide I-66

(R)-2-(6-(1H-indol-5-yl)- 1-oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-67

(R)-2-(6-(1H-indol-6-yl)- 1-oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-68

(R)-2-(1-oxo- 6-(4-(piperazin-1- yl)phenyl)isoindolin- 2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-69

(R)-2-(6-(4-(4- methylpiperazin-1- yl)phenyl)-1- oxoisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl) acetamide I-70

(R)-2-(1-oxo-6-(quinolin- 3-yl)isoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-71

(R)-2-(1-oxo- 6-(quinolin-8- yl)isoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-72

methyl (R)-4- (3-oxo-2-(2-oxo-1- phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin- 5-yl)benzoate I-73

(R)-2-(6-(3- aminophenyl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-74

(R)-2-(1-oxo-6-(4- (trifluoromethoxy) phenyl)isoindolin-2-yl)-2-phenyl-N-(thiazol- 2-yl)acetamide I-75

(R)-2-(6-(2- fluorophenyl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-76

(R)-2-(6-(3- fluorophenyl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-77

(R)-2-(6-(4- fluorophenyl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-78

(R)-4-(3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl)isoindolin-5-yl)benzoic acid I-79

(R)-2-(6-(3,5- dimethoxyphenyl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-80

(R)-2-(6-(2,4- dimethoxyphenyl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-81

(R)-N-(2- (dimethylamino)ethyl)-4- (3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino) ethyl)isoindolin- 5-yl)benzamide I-82

(R)-N-(4- (dimethylamino)butyl)-4- (3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino) ethyl)isoindolin- 5-yl)benzamide I-83

(R)-N-(2- morpholinoethyl)-4-(3- oxo-2-(2-oxo-1- phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin- 5-yl)benzamide I-84

(R)-N-(3- morpholinopropyl)-4-(3- oxo-2-(2-oxo-1- phenyl-2-(thiazol-2-ylamino)ethyl)isoindolin- 5-yl)benzamide I-85

(R)-2-(6-(4- (morpholine-4- carbonyl)phenyl)- 1-oxoisoindolin-2-yl)-2-phenyl-N-(thiazol- 2-yl)acetamide I-86

(R)-2-(6-(cyclohex- 1-en-1-yl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-87

(R)-N-benzyl-2- (1-oxoisoindolin-2- yl)-2-phenylacetamide I-88

(R)-N-(2- (dimethylamino)ethyl)-3- (3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino) ethyl)isoindolin- 5-yl)benzamide I-89

(R)-N-(4- (dimethylamino)butyl)- (3-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino) ethyl)isoindolin- 5-yl)benzamide I-90

(R)-N-(2- morpholinoethyl)-3-(3- oxo-2-(2-oxo-1- phenyl-2-(thiazol-2-ylamino)ethyl) isoindolin-5- yl)benzamide I-91

(R)-N-(3- morpholinopropyl)-3-(3- oxo-2-(2-oxo-1- phenyl-2-(thiazol-2-ylamino)ethyl) isoindolin-5- yl)benzamide I-92

(R)-2-(6-(3- (morpholine-4- carbonyl)phenyl)- 1-oxoisoindolin-2-yl)-2-phenyl-N-(thiazol- 2-yl)acetamide I-93

(R)-2-(1-oxo-5- (phenylamino) isoindolin-2-yl)-2- phenyl-N-(thiazol-2-yl)acetamide I-94

(R)-2-(5-((4- morpholinophenyl) amino)-1- oxoisoindolin- 2-yl)-2-phenyl-(thiazol-2-yl)acetamide I-95

(R)-2-(1-oxo- 5-((3-(pyrrolidin-1- ylmethyl)phenyl) amino)isoindolin-2-yl)-2-phenyl-N-(thiazol- 2-yl)acetamide I-96

(R)-2-(5-((4- (benzyloxy)phenyl)amino)- 1-oxoisoindolin-2-yl)-2-phenyl-N- (thiazol-2-yl)acetamide I-97

(R)-2-(5-((3- fluorophenyl)amino)-1- oxoisoindolin-2-yl)- 2-phenyl-N-(thiazol-2-yl)acetamide I-98

(R)-2-(1-oxo-6- (phenylamino) isoindolin-2-yl)-2- phenyl-N-(thiazol-2-yl)acetamide I-99

(R)-2-(6-((3- fluorophenyl)amino)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-100

(R)-2-(1-oxo-6- ((3-(pyrrolidin-1- ylmethyl)phenyl) amino)isoindolin-2-yl)-2-phenyl-N-(thiazol-2- yl)acetamide I-101

(R)-2-(5-(2- fluorophenyl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-102

(R)-2-(5-(4-(4- methylpiperazin-1- yl)phenyl)-1- oxoisoindolin-2-yl)-2-phenyl-N-(thiazol- 2-yl)acetamide I-103

(R)-2-(5-(2,3- dihydrobenzo[b] [1,4]dioxin-6-yl)-1- oxoisoindolin-2-yl)-2-phenyl-N- (thiazol-2-yl)acetamide I-104

(R)-2-(5- (1H-indol-5-yl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-105

(R)-2-(1-oxo-5- phenylisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-106

methyl (R)-5- bromo-2-((2-oxo-1- phenyl-2-(thiazol-2- ylamino)ethyl)amino)benzoate I-107

methyl (S)-5- bromo-2-((2-oxo-1- phenyl-2-(thiazol-2- ylamino)ethyl)amino)benzoate I-108

(R)-2-(1-oxo- 6-(pyridin-2- yl)isoindolin-2-yl)- 2-phenyl-N-(thiazol-2-yl)acetamide I-109

(R)-2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)-2-(3-nitrophenyl)-N-(thiazol-2- yl)acetamide I-110

N-(2,3- dihydroxypropyl)-2-nitro- 5-(((R)-2-oxo-1- phenyl-2-(thiazol-2-ylamino)ethyl) amino)benzamide I-111

5-bromo-N-(2,3- dihydroxypropyl)- 2-(((R)-2-oxo-1- phenyl-2-(thiazol-2-ylamino)ethyl) amino)benzamide I-112

(S)-2-(6-(1H-indol-5-yl)- 1-oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-113

(S)-2-(6-(2-fluorophenyl)- 1-oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-114

(S)-2-(6-(4-cyano- 3-fluorophenyl)- 1-oxoisoindolin-2- yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-115

(S)-2-(1-oxo- 6-(4-(piperazin-1- yl)phenyl)isoindolin- 2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide I-116

(R)-2-(6-(1H- indol-5-yl)-1- oxoisoindolin-2- yl)-N-(thiazol-2-yl)propanamide I-117

tert-butyl (R)-4- (4-(3-oxo-2-(1-oxo- 1-(thiazol-2- ylamino)propan-2-yl)isoindolin-5- yl)phenyl)piperazine- 1-carboxylate I-118

(R)-2-(1-oxo- 6-(4-(piperazin-1- yl)phenyl)isoindolin- 2-yl)-N-(thiazol-2-yl)propanamide I-119

tert-butyl (R)-4- (3-fluoro-4-(3-oxo- 2-(2-oxo-1-phenyl- 2-(thiazol-2-ylamino)ethyl) isoindolin-5- yl)phenyl)piperazine- 1-carboxylate I-120

(R)-2-(6-(2-fluoro- 4-(piperazin-1- yl)phenyl)-1- oxoisoindolin-2-yl)-2-phenyl-N-(thiazol- 2-yl)acetamide I-121

(R)-2-(1-oxo- 6-(4-(piperazin-1- ylmethyl)phenyl) isoindolin-2-yl)-2-phenyl-N-(thiazol- 2-yl)acetamide I-122

2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)-2-(3-fluorophenyl)-N-(thiazol- 2-yl)acetamide I-123

2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)- 2-(pyridin-2-yl)-N-(thiazol-2-yl)acetamide I-124

2-(1-oxo-6-(4-(piperazin-1- yl)phenyl)isoindolin-2-yl)-2-(pyridin-2-yl)-N-(thiazol-2- yl)acetamide I-125

2-(3-fluorophenyl)- 2-(1-oxo-6-(4- (piperazin-1-ylmethyl)phenyl)isoindolin- 2-yl)-N-(thiazol- 2-yl)acetamide I-126

(R)-2-(5-fluoro- 2-hydroxyphenyl)-2- (1-oxo-6-(4-(piperazin-1-yl)phenyl) isoindolin-2-yl)-N- (thiazol-2-yl)acetamide I-127

(R)-2-(6- (1H-indol-5-yl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(1,3,4-thiadiazol- 2-yl)acetamide I-128

(R)-2-(6-(1H- indol-5-yl)-1- oxoisoindolin-2- yl)-N-(isothiazol-4-yl)-2-phenylacetamide I-129

(R)-2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)- N-(oxazol-2-yl)-2-phenylacetamide I-130

(R)-2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)- N-(isoxazol-4-yl)-2-phenylacetamide I-131

(R)-2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)-N-(4-methylthiazol-2-yl)-2- phenylacetamide I-132

(R)-2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(4-(trifluoromethyl)thiazol-2- yl)acetamide I-133

(R)-2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)- N-(1H-imidazol-2-yl)-2-phenylacetamide I-134

(R)-2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2- yl)-2-phenyl-N-(pyrimidin-5-yl)acetamide I-135

2-(5-fluoro-2- hydroxyphenyl)-2-(6- (2-fluoro-4-(piperazin-1-yl)phenyl)- 1-oxoisoindolin-2- yl)-N-(thiazol-2- yl)acetamide I-136

2-(6-(1H-indazol-5-yl)-1- oxoisoindolin-2- yl)-2-(5-fluoro-2-hydroxyphenyl)-N-(thiazol- 2-yl)acetamide I-137

2-(5-fluoro-2- hydroxyphenyl)-2-(1- oxo-6-(1H-pyrrolo [2,3-b]pyridin-5-yl)isoindolin-2-yl)- N-(thiazol-2- yl)acetamide I-138

2-(2,5-difluorophenyl)- 2-(1-oxo-6- (4-(piperazin-1-yl)phenyl)isoindolin-2-yl)- N-(thiazol-2- yl)acetamide I-139

2-(2,5-difluorophenyl)- 2-(6-(2- fluoro-4-(piperazin- 1-yl)phenyl)-1-oxoisoindolin-2- yl)-N-(thiazol-2- yl)acetamide I-140

2-(6-(1H-indol-5-yl)-1- oxoisoindolin-2-yl)-2-(2,5-difluorophenyl)-N-(thiazol- 2-yl)acetamide I-141

2-(6-(1H-indazol-5-yl)-1- oxoisoindolin-2-yl)-2-(2,5-difluorophenyl)-N-(thiazol- 2-yl)acetamide I-142

2-(2,5-difluorophenyl)- 2-(1-oxo-6- (1H-pyrrolo[2,3-b] pyridin-5-yl)isoindolin-2-yl)- N-(thiazol-2- yl)acetamide I-143

2-(1-oxoisoindolin- 2-yl)-3-(pyridin- 3-yl)-N-(thiazol-2- yl)propanamideI-144

3-(3-hydroxyphenyl)-2- (1-oxoisoindolin-2- yl)-N-(thiazol-2-yl)propanamide I-145

2-(6-(2-chloro- 4-(piperazin-1- yl)phenyl)-1- oxoisoindolin-2-yl)-2-(5-fluoro-2- hydroxyphenyl)-N- (thiazol-2-yl)acetamide I-146

2-(5-fluoro-2- hydroxyphenyl)-2-(6- (2-methoxy-4-(piperazin-1-yl)phenyl)-1- oxoisoindolin-2-yl)-N- (thiazol-2-yl)acetamide I-147

2-(6-(1H-indol-5-yl)- 1-oxoisoindolin- 2-yl)-2-(5-fluoro-hydroxyphenyl)- N-(thiazol-2- yl)acetamide I-148

2-(5-fluoro-2- hydroxyphenyl)-2-(6- (4-(4-(2-hydroxyethyl) piperazin-1-yl)phenyl)-1- oxoisoindolin-2-yl)-N- (thiazol-2-yl)acetamide I-149

2-(5-fluoro-2- hydroxyphenyl)-2-(6- (4-(4-(2-hydroxyacetyl) piperazin-1-yl)phenyl)-1- oxoisoindolin-2-yl)-N- (thiazol-2-yl)acetamide I-150

2-(5-fluoro-2- hydroxyphenyl)-2-(1- oxo-6-(4-(4- sulfamoylpiperazin-1-yl)phenyl) isoindolin-2-yl)-N- (thiazol-2-yl)acetamide I-151

2-(6-(4-(4-(dimethylamino) piperidin-1-yl)phenyl)-1- oxoisoindolin-2-yl)-2-(5-fluoro-2- hydroxyphenyl)- N-(thiazol-2- yl)acetamide I-152

2-(5-fluoro-2- hydroxyphenyl)-2-(6- (2-(2-hydroxyethoxy)- 4-(piperazin-1-yl)phenyl)-1- oxoisoindolin-2-yl)- N-(thiazol-2-yl)acetamide I-153

2-(5-fluoro-2- hydroxyphenyl)-2-(7- (2-hydroxyethoxy)-1-oxo-6-(4-(piperazin-1-yl) phenyl)isoindolin-2- yl)-N-(thiazol-2-yl) acetamideI-154

2-(5-fluoro-2- hydroxyphenyl)-2-(1- oxo-7-(piperazin- 1-yl)-1,3-dihydro-2H-benzo[e] isoindol-2-yl)-N- (thiazol-2-yl)acetamide I-155

2-(5-fluoro-2- (hydroxymethyl) phenyl)-2-(1-oxo- 5-(4-(piperazin-1-yl)phenyl)isoindolin-2-yl)- N-(thiazol-2-yl)acetamide I-156

2-(5-fluoro-2- mercaptophenyl)-2-(1- oxo-5-(4-(piperazin-1-yl)phenyl)isoindolin-2-yl)-N- (thiazol-2-yl)acetamide I-157

2-(5-fluoro-2- sulfamoylphenyl)-2- (1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindolin-2-yl)- N-(thiazol-2-yl)acetamide I-158

2-(2-hydroxyphenyl)-2- (1-oxoisoindolin-2- yl)-N-(thiazol-2-yl)propanamide I-159

(R)-2-(5-fluoro-2- hydroxyphenyl)-2- (1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindolin-2-yl)-N- (thiazol-2-yl)propanamide

A compound that binds to an allosteric site in EGFR or ERBB2, such asthe compounds of the present disclosure (e.g., the compounds of theformulae disclosed herein), optionally in combination with a secondagent wherein said second agent prevents EGFR dimer formation, arecapable of modulating EGFR activity. In some embodiments, the compoundsof the present disclosure are capable of inhibiting or decreasing EGFRactivity, without a second agent (e.g., an antibody such as cetuximab,trastuzumab, or panitumumab). In other embodiments, the compounds of thepresent disclosure in combination with a second agent wherein saidsecond agent prevents EGFR dimer formation and are capable of inhibitingor decreasing EGFR activity. In some embodiments, the second agent thatprevents EGFR dimer formation is an antibody. In further embodiments,the second agent that prevents EGFR dimer formation is cetuximab,trastuzumab, or panitumumab. In further embodiments, the second agentthat prevents EGFR dimer formation is cetuximab.

In some embodiments, the compounds of the present disclosure are capableof modulating (e.g., inhibiting or decreasing) the activity of EGFRcontaining one or more mutations. In some embodiments, the mutant EGFRcontains one or more mutations selected from T790M, L718Q, L844V, V948R,L858R, I941R, C797S, and Del. In other embodiments, the mutant EGFRcontains a combination of mutations, wherein the combination is selectedfrom Del/L718Q, Del/L844V, Del/T790M, Del/T790M/L718Q, Del/T790M/L844V,L858R/L718Q, L858R/L844V, L858R/T790M, L858R/T790M/I941R, Del/T790M,Del/T790M/C797S, L858R/T790M/C797S, and L858R/T790M/L718Q. In otherembodiments, the mutant EGFR contains a combination of mutations,wherein the combination is selected from Del/L844V, L858R/L844V,L858R/T790M, L858R/T790M/I941R, L858R/T790M/C797S, Del/T790M, Del/T790M,Del/T790M/C797S, and L858R/T790M. In other embodiments, the mutant EGFRcontains a combination of mutations, wherein the combination is selectedfrom L858R/T790M, L858R/T790M/I941R, L858R/T790M/C797S, Del/T790M,Del/T790M/C797S, and L858R/T790M.

In some embodiments, the compounds of the present disclosure incombination with a second agent wherein said second agent prevents EGFRdimer formation are capable of modulating (e.g., inhibiting ordecreasing) the activity of EGFR containing one or more mutations. Insome embodiments, the mutant EGFR contains one or more mutationsselected from T790M, L718Q, L844V, V948R, L858R, I941R, C797S, and Del.In other embodiments, the mutant EGFR contains a combination ofmutations, wherein the combination is selected from Del/L718Q,Del/L844V, Del/T790M, Del/T790M/L718Q, Del/T790M/L844V, L858R/L718Q,L858R/L844V, L858R/T790M, L858R/T790M/I941R, Del/T790M, Del/T790M/C797S,L858R/T790M/C797S, and L858R/T790M/L718Q. In other embodiments, themutant EGFR contains a combination of mutations, wherein the combinationis selected from Del/L844V, L858R/L844V, L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M. In otherembodiments, the mutant EGFR contains a combination of mutations,wherein the combination is selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M. In someembodiments, the second agent that prevents EGFR dimer formation is anantibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

In some embodiments, the compounds of the present disclosure are capableof modulating (e.g., inhibiting or decreasing) the activity of EGFRcontaining one or more mutations, but do not affect the activity of awild-type EGFR.

In other embodiments, the compounds of the present disclosure incombination with a second agent wherein said second agent prevents EGFRdimer formation are capable of modulating (e.g., inhibiting ordecreasing) the activity of EGFR containing one or more mutations, butdo not affect the activity of a wild-type EGFR. In some embodiments, thesecond agent that prevents EGFR dimer formation is an antibody. Infurther embodiments, the second agent that prevents EGFR dimer formationis cetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

Modulation of EGFR containing one or more mutations, such as thosedescribed herein, but not a wild-type EGFR, provides a novel approach tothe treatment, prevention, or amelioration of diseases including, butnot limited to, cancer and metastasis, inflammation, arthritis, systemiclupus erthematosus, skin-related disorders, pulmonary disorders,cardiovascular disease, ischemia, neurodegenerative disorders, liverdisease, gastrointestinal disorders, viral and bacterial infections,central nervous system disorders, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, spinalcord injury, and peripheral neuropathy.

In some embodiments, the compounds of the disclosure exhibit greaterinhibition of EGFR containing one or more mutations as described hereinrelative to a wild-type EGFR. In certain embodiments, the compounds ofthe disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold,25-fold, 50-fold or 100-fold greater inhibition of EGFR containing oneor more mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the disclosure exhibit up to1000-fold greater inhibition of EGFR containing one or more mutations asdescribed herein relative to a wild-type EGFR. In various embodiments,the compounds of the disclosure exhibit up to 10000-fold greaterinhibition of EGFR having a combination of mutations described herein(e.g., L858R/T790M, L858R/T790M/I941R, L858R/T790M/C797S, Del/T790M,Del/T790M/C797S, and L858R/T790M) relative to a wild-type EGFR.

In other embodiments, the compounds of the disclosure in combinationwith a second agent wherein said second agent prevents EGFR dimerformation exhibit greater inhibition of EGFR containing one or moremutations as described herein relative to a wild-type EGFR. In certainembodiments, the compounds of the disclosure in combination with asecond agent wherein said second agent prevents EGFR dimer formationexhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or100-fold greater inhibition of EGFR containing one or more mutations asdescribed herein relative to a wild-type EGFR. In various embodiments,the compounds of the disclosure in combination with a second agentwherein said second agent prevents EGFR dimer formation exhibit up to1000-fold greater inhibition of EGFR containing one or more mutations asdescribed herein relative to a wild-type EGFR. In various embodiments,the compounds of the disclosure in combination with a second agentwherein said second agent prevents EGFR dimer formation exhibit up to10000-fold greater inhibition of EGFR having a combination of mutationsdescribed herein (e.g., L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M) relativeto a wild-type EGFR. In some embodiments, the second agent that preventsEGFR dimer formation is an antibody. In further embodiments, the secondagent that prevents EGFR dimer formation is cetuximab, trastuzumab, orpanitumumab. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab.

In some embodiments, the compounds of the disclosure exhibit from about2-fold to about 10-fold greater inhibition of EGFR containing one ormore mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the disclosure exhibit from about10-fold to about 100-fold greater inhibition of EGFR containing one ormore mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the disclosure exhibit from about100-fold to about 1000-fold greater inhibition of EGFR containing one ormore mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the disclosure exhibit from about1000-fold to about 10000-fold greater inhibition of EGFR containing oneor more mutations as described herein relative to a wild-type EGFR.

In other embodiments, the compounds of the disclosure in combinationwith a second agent wherein said second agent prevents EGFR dimerformation exhibit from about 2-fold to about 10-fold greater inhibitionof EGFR containing one or more mutations as described herein relative toa wild-type EGFR. In other embodiments, the compounds of the disclosurein combination with a second agent wherein said second agent preventsEGFR dimer formation exhibit from about 10-fold to about 100-foldgreater inhibition of EGFR containing one or more mutations as describedherein relative to a wild-type EGFR. In other embodiments, the compoundsof the disclosure in combination with a second agent wherein said secondagent prevents EGFR dimer formation exhibit from about 100-fold to about1000-fold greater inhibition of EGFR containing one or more mutations asdescribed herein relative to a wild-type EGFR. In other embodiments, thecompounds of the disclosure in combination with a second agent whereinsaid second agent prevents EGFR dimer formation exhibit from about1000-fold to about 10000-fold greater inhibition of EGFR containing oneor more mutations as described herein relative to a wild-type EGFR. Inother embodiments, the second agent that prevents EGFR dimer formationis an antibody. In further embodiments, the second agent that preventsEGFR dimer formation is cetuximab, trastuzumab, or panitumumab. Infurther embodiments, the second agent that prevents EGFR dimer formationis cetuximab.

In certain embodiments, the compounds of the disclosure exhibit at least2-fold greater inhibition of EGFR having a combination of mutationsselected from L858R/T790M, L858R/T790M/I941R, L858R/T790M/C797S,Del/T790M, Del/T790M/C797S, and L858R/T790M relative to a wild-typeEGFR. In certain embodiments, the compounds of the disclosure exhibit atleast 3-fold greater inhibition of EGFR having a combination ofmutations selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure exhibit at least 5-fold greater inhibition of EGFR having acombination of mutations selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure exhibit at least 10-fold greater inhibition of EGFR having acombination of mutations selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure exhibit at least 25-fold greater inhibition of EGFR having acombination of mutations selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure exhibit at least 50-fold greater inhibition of EGFR having acombination of mutations selected from L L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure exhibit at least 100-fold greater inhibition of EGFR having acombination of mutations selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR.

In certain embodiments, the compounds of the disclosure in combinationwith a second agent wherein said second agent prevents EGFR dimerformation exhibit at least 2-fold greater inhibition of EGFR having acombination of mutations selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure in combination with a second agent wherein said second agentprevents EGFR dimer formation exhibit at least 3-fold greater inhibitionof EGFR having a combination of mutations selected from L858R/T790M,L858R/T790M/I941R, L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, andL858R/T790M relative to a wild-type EGFR. In certain embodiments, thecompounds of the disclosure in combination with a second agent whereinsaid second agent prevents EGFR dimer formation exhibit at least 5-foldgreater inhibition of EGFR having a combination of mutations selectedfrom L858R/T790M, L858R/T790M/I941R, L858R/T790M/C797S, Del/T790M,Del/T790M/C797S, and L858R/T790M relative to a wild-type EGFR. Incertain embodiments, the compounds of the disclosure in combination witha second agent wherein said second agent prevents EGFR dimer formationexhibit at least 10-fold greater inhibition of EGFR having a combinationof mutations selected from L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure in combination with a second agent wherein said second agentprevents EGFR dimer formation exhibit at least 25-fold greaterinhibition of EGFR having a combination of mutations selected fromL858R/T790M, L858R/T790M/I941R, L858R/T790M/C797S, Del/T790M,Del/T790M/C797S, and L858R/T790M relative to a wild-type EGFR. Incertain embodiments, the compounds of the disclosure in combination witha second agent wherein said second agent prevents EGFR dimer formationexhibit at least 50-fold greater inhibition of EGFR having a combinationof mutations selected from L L858R/T790M, L858R/T790M/I941R,L858R/T790M/C797S, Del/T790M, Del/T790M/C797S, and L858R/T790M relativeto a wild-type EGFR. In certain embodiments, the compounds of thedisclosure in combination with a second agent wherein said second agentprevents EGFR dimer formation exhibit at least 100-fold greaterinhibition of EGFR having a combination of mutations selected fromL858R/T790M, L858R/T790M/I941R, L858R/T790M/C797S, Del/T790M,Del/T790M/C797S, and L858R/T790M relative to a wild-type EGFR. In someembodiments, the second agent that prevents EGFR dimer formation is anantibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

In some embodiments, the inhibition of EGFR activity is measured byIC₅₀.

In some embodiments, the inhibition of EGFR activity is measured byEC₅₀.

In some embodiments, the compounds of the disclosure bind to anallosteric site in EGFR. In some embodiments, the compounds of thedisclosure interact with at least one amino acid residue of epidermalgrowth factor receptor (EGFR) selected from Lys745, Leu788, and Ala 743.In other embodiments, the compounds of the disclosure interact with atleast one amino acid residue of epidermal growth factor receptor (EGFR)selected from Cys755, Leu777, Phe856, and Asp855. In other embodiments,the compounds of the disclosure interact with at least one amino acidresidue of epidermal growth factor receptor (EGFR) selected from Met766,Ile759, Glu762, and Ala763. In other embodiments, the compounds of thedisclosure interact with at least one amino acid residue of epidermalgrowth factor receptor (EGFR) selected from Lys745, Leu788, and Ala 743,at least one amino acid residue of epidermal growth factor receptor(EGFR) selected from Cys755, Leu777, Phe856, and Asp855, and at leastone amino acid residue of epidermal growth factor receptor (EGFR)selected from Met766, Ile759, Glu762, and Ala763. In other embodiments,the compounds of the disclosure do not interact with the any of theamino acid residues of epidermal growth factor receptor (EGFR) selectedfrom Met793, Gly796, and Cys797.

In some embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor, wherein the compound is a more potentinhibitor of a drug-resistant EGFR mutant relative to a wild type EGFR.For example, the compound can be at least about 2-fold, 3-fold, 5-fold,10-fold, 25-fold, 50-fold or about 100-fold more potent at inhibitingthe kinase activity of the drug-resistant EGFR mutant relative to awild-type EGFR. In some embodiments, the drug-resistant EGFR mutant isresistant to one or more known EGFR inhibitors, including but notlimited to gefitinib, erlotinib, lapatinib, WZ4002:

In some embodiments, the drug-resistant EGFR mutant comprises asensitizing mutation, such as Del and L858R.

In some embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor in combination with a second agent whereinsaid second agent prevents EGFR dimer formation, wherein the compound isa more potent inhibitor of a drug-resistant EGFR mutant relative to awild type EGFR. For example, the compound in combination with a secondagent wherein said second agent prevents EGFR dimer formation can be atleast about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about100-fold more potent at inhibiting the kinase activity of thedrug-resistant EGFR mutant relative to a wild-type EGFR. In someembodiments, the drug-resistant EGFR mutant is resistant to one or moreknown EGFR inhibitors, including but not limited to gefitinib,erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and AZD9291. In someembodiments, the drug-resistant EGFR mutant comprises a sensitizingmutation, such as Del and L858R. In some embodiments, the second agentthat prevents EGFR dimer formation is an antibody. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In some embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor, wherein the compound inhibits kinaseactivity of a drug-resistant EGFR mutant harboring a sensitizingmutation (e.g., Del and L858R) and a drug-resistance mutation (e.g.,T790M, L718Q, C797S, and L844V) with less than a 10-fold difference inpotency (e.g., as measured by IC₅₀) relative to an EGFR mutant harboringthe sensitizing mutation but not the drug-resistance mutation. In someembodiments, the difference in potency is less than about 9-fold,8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold.

In other embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor in combination with a second agent whereinsaid second agent prevents EGFR dimer formation, wherein the compound incombination with the second agent inhibits kinase activity of adrug-resistant EGFR mutant harboring a sensitizing mutation (e.g., Deland L858R) and a drug-resistance mutation (e.g., T790M, L718Q, C797S,and L844V) with less than a 10-fold difference in potency (e.g., asmeasured by IC₅₀) relative to an EGFR mutant harboring the sensitizingmutation but not the drug-resistance mutation. In some embodiments, thedifference in potency is less than about 9-fold, 8-fold, 7-fold, 6-fold,5-fold, 4-fold, 3-fold, or 2-fold. In some embodiments, the second agentthat prevents EGFR dimer formation is an antibody. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In some embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor, wherein the compound is more potent thanone or more known EGFR inhibitors, including but not limited togefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, andAZD9291, at inhibiting the activity of EGFR containing one or moremutations as described herein, such as T790M, L718Q, L844V, L858R,C797S, and Del. For example, the compound can be at least about 2-fold,3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent(e.g., as measured by IC₅₀) than gefitinib, erlotinib, lapatinib,WZ4002, HKI-272, CL-387785, and AZD9291 at inhibiting the activity ofthe EGFR containing one or more mutations as described herein.

In other embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor in combination with a second agent whereinsaid second agent prevents EGFR dimer formation, wherein the compound incombination with the second agent is more potent than one or more knownEGFR inhibitors, including but not limited to gefitinib, erlotinib,lapatinib, WZ4002, HKI-272, CL-387785, and AZD9291, at inhibiting theactivity of EGFR containing one or more mutations as described herein,such as T790M, L718Q, L844V, L858R, C797S, and Del. For example, thecompound in combination with a second agent wherein said second agentprevents EGFR dimer formation can be at least about 2-fold, 3-fold,5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g.,as measured by IC₅₀) than gefitinib, erlotinib, lapatinib, WZ4002,HKI-272, CL-387785, and AZD9291 at inhibiting the activity of the EGFRcontaining one or more mutations as described herein. In someembodiments, the second agent that prevents EGFR dimer formation is anantibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

In some embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor, wherein the compound is less potent thanone or more known EGFR inhibitors, including but not limited togefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, andAZD9291, at inhibiting the activity of a wild-type EGFR. For example,the compound can be at least about 2-fold, 3-fold, 5-fold, 10-fold,25-fold, 50-fold or about 100-fold less potent (e.g., as measured byIC₅₀) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785,and AZD9291, at inhibiting the activity of a wild-type EGFR.

In other embodiments, the disclosure provides a compound comprising anallosteric kinase inhibitor in combination with a second agent whereinsaid second agent prevents EGFR dimer formation, wherein the compound incombination with the second agent is less potent than one or more knownEGFR inhibitors, including but not limited to gefitinib, erlotinib,lapatinib, WZ4002, HKI-272, CL-387785, and AZD9291, at inhibiting theactivity of a wild-type EGFR. For example, the compound in combinationwith a second agent wherein said second agent prevents EGFR dimerformation can be at least about 2-fold, 3-fold, 5-fold, 10-fold,25-fold, 50-fold or about 100-fold less potent (e.g., as measured byIC₅₀) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785,and AZD9291, at inhibiting the activity of a wild-type EGFR. In someembodiments, the second agent that prevents EGFR dimer formation is anantibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

Potency of the inhibitor can be determined by EC₅₀ value. A compoundwith a lower EC₅₀ value, as determined under substantially similarconditions, is a more potent inhibitor relative to a compound with ahigher EC₅₀ value. In some embodiments, the substantially similarconditions comprise determining an EGFR-dependent phosphorylation level,in vitro or in vivo (e.g., in 3T3 cells expressing a wild type EGFR, amutant EGFR, or a fragment of any thereof).

Potency of the inhibitor can also be determined by IC₅₀ value. Acompound with a lower IC₅₀ value, as determined under substantiallysimilar conditions, is a more potent inhibitor relative to a compoundwith a higher IC₅₀ value. In some embodiments, the substantially similarconditions comprise determining an EGFR-dependent phosphorylation level,in vitro or in vivo (e.g., in 3T3 cells expressing a wild type EGFR, amutant EGFR, or a fragment of any thereof).

An EGFR sensitizing mutation comprises without limitation L858R, G719S,G719C, G719A, L861Q, a deletion in exon 19 and/or an insertion in exon20. A drug-resistant EGFR mutant can have without limitation a drugresistance mutation comprising T790M, T854A, L718Q, C797S, or D761Y.

The selectivity between wild-type EGFR and EGFR containing one or moremutations as described herein can also be measured using cellularproliferation assays where cell proliferation is dependent on kinaseactivity. For example, murine Ba/F3 cells transfected with a suitableversion of wild-type EGFR (such as VIII; containing a WT EGFR kinasedomain), or Ba/F3 cells transfected with L858R/T790M, Del/T790M/L718Q,L858R/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S,L858R/T790M/I941R, or Exon 19 deletion/T790M can be used. Proliferationassays are performed at a range of inhibitor concentrations (10 μM, 3μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, I nM) and an EC₅₀ iscalculated.

An alternative method to measure effects on EGFR activity is to assayEGFR phosphorylation. Wild type or mutant (L858R/T790M, Del/T790M,Del/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R,or L858R/T790M/L718Q) EGFR can be transfected into NIH-3T3 cells (whichdo not normally express endogenous EGFR) and the ability of theinhibitor (using concentrations as above) to inhibit EGFRphosphorylation can be assayed. Cells are exposed to increasingconcentrations of inhibitor for 6 hours and stimulated with EGF for 10minutes. The effects on EGFR phosphorylation are assayed by WesternBlotting using phospho-specific (Y1068) EGFR antibodies.

In another aspect, the present disclosure relates to a compound thatbinds to an allosteric site in EGFR, wherein the compound exhibitsgreater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold,100-fold, or 1000-fold inhibition of EGFR containing one or moremutations as described herein (e.g., L858R/T790M, Del/T790M,Del/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R,or L858R/T790M/L718Q) relative to a wild-type EGFR.

In other embodiments, the disclosure provides a compound that binds toan allosteric site in EGFR in combination with a second agent whereinsaid second agent prevents EGFR dimer formation, wherein the compound incombination with the second agent greater than 2-fold, 3-fold, 5-fold,10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold inhibition of EGFRcontaining one or more mutations as described herein (e.g., L858R/T790M,Del/T790M, Del/T790M/L718Q, Del/T790M/C797S, L858R/T790M/C797S,L858R/T790M/I941R, or L858R/T790M/L718Q) relative to a wild-type EGFR.In some embodiments, the second agent that prevents EGFR dimer formationis an antibody. In further embodiments, the second agent that preventsEGFR dimer formation is cetuximab, trastuzumab, or panitumumab. Infurther embodiments, the second agent that prevents EGFR dimer formationis cetuximab.

Definitions

Listed below are definitions of various terms used to describe thisdisclosure. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals containing, in certain embodiments,between one and six, or one and eight carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl radicals; and examples of C₁-C₈ alkyl radicals include, but arenot limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, heptyl, octyl radicals.

The term “alkenyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing, in certain embodiments, from twoto six, or two to eight carbon atoms having at least one carbon-carbondouble bond. The double bond may or may not be the point of attachmentto another group. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

The term “alkynyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing, in certain embodiments, from twoto six, or two to eight carbon atoms having at least one carbon-carbontriple bond. The alkynyl group may or may not be the point of attachmentto another group. Representative alkynyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl and the like.

The term “alkoxy” refers to an —O-alkyl radical.

The term “aryl,” as used herein, refers to a mono- or poly-cycliccarbocyclic ring system having one or more aromatic rings, fused ornon-fused, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like.

The term “aralkyl,” as used herein, refers to an alkyl residue attachedto an aryl ring. Examples include, but are not limited to, benzyl,phenethyl and the like.

The term “cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated or partiallyunsaturated carbocyclic ring compound. Examples of C₃-C₈ cycloalkylinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.Also contemplated is a monovalent group derived from a monocyclic orpolycyclic carbocyclic ring compound having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Examples of suchgroups include, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

The term “heteroaryl,” as used herein, refers to a mono- or poly-cyclic(e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ringsystem having at least one aromatic ring, having from five to ten ringatoms of which one ring atoms is selected from S, O, and N; zero, one,or two ring atoms are additional heteroatoms independently selected fromS, O, and N; and the remaining ring atoms are carbon. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “heteroaralkyl,” as used herein, refers to an alkyl residueattached to a heteroaryl ring. Examples include, but are not limited to,pyridinylmethyl, pyrimidinylethyl and the like.

The term “heterocyclyl,” or “heterocycloalkyl,” as used herein, refersto a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- ortri-cyclic group fused of non-fused system, where (i) each ring containsbetween one and three heteroatoms independently selected from oxygen,sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bondsand each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen andsulfur heteroatoms may optionally be oxidized, and (iv) the nitrogenheteroatom may optionally be quaternized. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl), e.g., —NH(C₁-C₆ alkyl), where C₁-C₁₂ alkyl is as previouslydefined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl)₂, e.g., —NH(C₁-C₆ alkyl), where C₁-C₁₂ alkyl is as previouslydefined.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

In accordance with the disclosure, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

The terms “hal,” “halo,” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

As described herein, compounds of the disclosure may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the disclosure. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. The terms “optionally substituted”, “optionally substitutedalkyl,” “optionally substituted “optionally substituted alkenyl,”“optionally substituted alkynyl”, “optionally substituted cycloalkyl,”“optionally substituted cycloalkenyl,” “optionally substituted aryl”,“optionally substituted heteroaryl,” “optionally substituted aralkyl”,“optionally substituted heteroaralkyl,” “optionally substitutedheterocycloalkyl,” and any other optionally substituted group as usedherein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to:

—F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-Cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, NHC(O)NH₂,—NHC(O)NH—C₁i-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH— C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl,—NHC(NH)—C₁i-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl,—NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

It is understood that the aryls, heteroaryls, alkyls, and the like canbe substituted.

The term “cancer” includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia (acute and chronic), acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

The term “EGFR” herein refers to epidermal growth factor receptorkinase.

The term “HER” or “Her”, herein refers to human epidermal growth factorreceptor kinase.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

As used herein, “preventing” or “prevent” describes reducing oreliminating the onset of the symptoms or complications of the disease,condition or disorder.

As used herein, the term “allosteric site” refers to a site on EGFRother than the ATP binding site, such as that characterized in a crystalstructure of EGFR. An “allosteric site” can be a site that is close tothe ATP binding site, such as that characterized in a crystal structureof EGFR. For example, one allosteric site includes one or more of thefollowing amino acid residues of epidermal growth factor receptor(EGFR): Lys745, Leu788, Ala 743, Cys755, Leu777, Phe856, Asp855, Met766,Ile759, Glu762, and/or Ala763.

As used herein, the term “agent that prevents EGFR dimer formation”refers to an agent that prevents dimer formation in which the C-lobe ofthe “activator” subunit impinges on the N-lobe of the “receiver”subunit. Examples of agents that prevent EGFR dimer formation include,but are not limited to, cetuximab, cobimetinib, trastuzumab,panitumumab, and Mig6.

As used herein the term “GDC0973” or “Cobimetinib” refers to a compoundhaving the chemical structure:

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentdisclosure which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in JPharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of thedisclosure, or separately by reacting the free base function with asuitable organic acid.

Examples of pharmaceutically acceptable include, but are not limited to,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present disclosurewhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentdisclosure which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present disclosure. “Prodrug”, as used hereinmeans a compound which is convertible in vivo by metabolic means (e.g.,by hydrolysis) to afford any compound delineated by the formulae of theinstant disclosure. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

This disclosure also encompasses pharmaceutical compositions containing,and methods of treating disorders through administering,pharmaceutically acceptable prodrugs of compounds of the disclosure. Forexample, compounds of the disclosure having free amino, amido, hydroxyor carboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the disclosure. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities

Combinations of substituents and variables envisioned by this disclosureare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The disclosure also provides for a pharmaceutical composition comprisinga compound of disclosed herein, or a pharmaceutically acceptable ester,salt, or prodrug thereof, together with a pharmaceutically acceptablecarrier.

In another aspect, the disclosure provides a kit comprising a compoundcapable of inhibiting EGFR activity selected from one or more compoundsof disclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, optionally incombination with a second agent wherein said second agent prevents EGFRdimer formation and instructions for use in treating cancer.

In another aspect, the disclosure provides a method of synthesizing acompound of disclosed herein.

The synthesis of the compounds of the disclosure can be found herein andin the Examples below.

Other embodiments are a method of making a compound of any of theformulae herein using any one, or combination of, reactions delineatedherein. The method can include the use of one or more intermediates orchemical reagents delineated herein.

Another aspect is an isotopically labeled compound of any of theformulae delineated herein. Such compounds have one or more isotopeatoms which may or may not be radioactive (e.g., ³H, ²H, ¹⁴C, ¹³C, ¹⁸F,³⁵S, ³²P, ¹²⁵I, and ¹³¹I) introduced into the compound. Such compoundsare useful for drug metabolism studies and diagnostics, as well astherapeutic applications.

A compound of the disclosure can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the disclosure can be prepared by reacting the free acidform of the compound with a pharmaceutically acceptable inorganic ororganic base.

Alternatively, the salt forms of the compounds of the disclosure can beprepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the disclosure canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the disclosure in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the disclosure in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Prodrugs of the compounds of the disclosure can be prepared by methodsknown to those of ordinary skill in the art (e.g., for further detailssee Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound of the disclosure with a suitablecarbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the disclosure can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3rd edition, John Wiley and Sons, Inc.,1999.

Compounds of the present disclosure can be conveniently prepared, orformed during the process of the disclosure, as solvates (e.g.,hydrates). Hydrates of compounds of the present disclosure can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

In addition, some of the compounds of this disclosure have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, or as(D)- or (L)- for amino acids. All such isomeric forms of these compoundsare expressly included in the present disclosure.

Optical isomers may be prepared from their respective optically activeprecursors by the procedures described herein, or by resolving theracemic mixtures. The resolution can be carried out in the presence of aresolving agent, by chromatography or by repeated crystallization or bysome combination of these techniques which are known to those skilled inthe art. Further details regarding resolutions can be found in Jacques,et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons,1981).

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisdisclosure include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine.

The compounds of this disclosure may also be represented in multipletautomeric forms, in such instances, the disclosure expressly includesall tautomeric forms of the compounds described herein (e.g., alkylationof a ring system may result in alkylation at multiple sites, thedisclosure expressly includes all such reaction products). When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion. All such isomeric forms of suchcompounds are expressly included in the present disclosure.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent disclosure includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like.

Furthermore, so-called metabolite which is produced by degradation ofthe present compound in vivo is included in the scope of the presentdisclosure.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

Additionally, the compounds of the present disclosure, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules.Non-limiting examples of hydrates include monohydrates, dihydrates, etc.Non-limiting examples of solvates include ethanol solvates, acetonesolvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent disclosure. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this disclosure may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The compounds of the disclosure are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Method of Synthesizing the Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. The synthetic processes of thedisclosure can tolerate a wide variety of functional groups, thereforevarious substituted starting materials can be used. The processesgenerally provide the desired final compound at or near the end of theoverall process, although it may be desirable in certain instances tofurther convert the compound to a pharmaceutically acceptable salt,ester or prodrug thereof. Suitable synthetic routes are depicted in theschemes below.

Compounds of the present disclosure can be prepared in a variety of waysusing commercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentdisclosure.

The compounds of disclosed herein may be prepared by methods known inthe art of organic synthesis as set forth in part by the followingsynthetic schemes. In the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles or chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, Third edition, Wiley, New York 1999). These groupsare removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art. Theselection processes, as well as the reaction conditions and order oftheir execution, shall be consistent with the preparation of compoundsof disclosed herein.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of disclosed herein. Accordingly, the present disclosureincludes both possible stereoisomers (unless specified in the synthesis)and includes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

All the abbreviations used in this application are found in “ProtectiveGroups in Organic Synthesis” by John Wiley & Sons, Inc, or the MERCKINDEX by MERCK & Co., Inc, or other chemistry books or chemicalscatalogs by chemicals vendor such as Aldrich, or according to usage knowin the art.

The compounds of the present disclosure can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent disclosure can be synthesized by following the steps outlined inGeneral Schemes 1-3 which comprise different sequences of assemblingintermediates Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, and Il. Startingmaterials are either commercially available or made by known proceduresin the reported literature or as illustrated.

wherein R₁-R₄, R₂₂, m and n are defined herein.

The general way of preparing representative compounds of the presentdisclosure (i.e., Compound (I′) shown above) using intermediates Ib, Ic,Id, Ie, If, and Ig is outlined in General Scheme 1. Cyclization of Iband Ic using an acid, e.g., acetic acid, in solvent, e.g., CHCl₃, atelevated temperatures provides intermediate Ie. Alternatively,Intermediate Ie can be obtained via cyclization of Ib and Id using abase, e.g., N,N-diisopropylethylamine (DIPEA) in a solvent, e.g.,dimethylformamide (DMF) at elevated temperatures. Hydrolysis ofIntermediate Ie using a base, e.g., lithium hydroxide (LiOH) in asolvent, e.g., tetrahydrofuran (THF), methanol (MeOH), and/or water(H₂O), provides If. Coupling of acid If and amine Ig under standardcoupling conditions using a coupling reagent, e.g.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF, provides Compound(I′).

wherein R₁-R₄, R₁₅, R₁₆, m and n are defined herein.

The general way of preparing representative compounds of the presentdisclosure (i.e., Compound (I′) shown above) using intermediates Ig, Ih,Ii, and Ij is outlined in General Scheme 2. Nucleophilic addition of Ihto Ii using a base, e.g., potassium carbonate (K₂CO₃), in solvent, e.g.,DMF, at elevated temperatures provides intermediate Ij. Coupling ofcarboxylic acid Ij with amine Ig under standard coupling conditionsusing a coupling reagent, e.g.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF, provides Compound(I′).

wherein R₁-R₄, R₁₅, R₁₆, m and n are defined herein.

The general way of preparing representative compounds of the presentdisclosure (i.e., Compound (I′) shown above) using intermediates Ig, Ih,Ik, and Il is outlined in General Scheme 3. Acylation of amine Ih withIk using a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane, DMF provides intermediateIl. Coupling of carboxylic acid Il with amine Ig under standard couplingconditions using a coupling reagent, e.g.,[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF, provides Compound(I′).

A mixture of enantiomers, diastereomers, and/or cis/trans isomersresulting from the processes described above can be separated into theirsingle components by chiral salt technique, chromatography using normalphase, or reverse phase or chiral column, depending on the nature of theseparation.

It should be understood that in the description and formulae shownabove, the various groups R₁-R₄, R₁₅, R₁₆, R₂₂, m and n and othervariables are as defined herein, except where otherwise indicated.Furthermore, for synthetic purposes, the compounds of General Schemes1-3 are mere representatives with elected radicals to illustrate thegeneral synthetic methodology of the compounds of disclosed herein.

Biological Assays

Biochemical Assays

EGFR biochemical assays are carried out using a homogeneoustime-resolved fluorescence (HTRF) assay. The reaction mixtures containbiotin-Lck-peptide substrate, wild type, or mutant EGFR enzyme inreaction buffer. Enzyme concentrations are adjusted to accommodatevarying kinase activity and ATP concentrations. Compounds of the presentdisclosure are diluted into the assay mixture and IC₅₀ values aredetermined using 12-point inhibition curves.

Phospho-EGFR Target Modulation Assays and ELISA

Cells are lysed with lysis buffer containing protease and phosphataseinhibitors and the plates are shaken. An aliquot from each well is thentransferred to prepared ELISA plates for analysis. Once harvested andplated, the cells are pre-treated with media with or without EGF. Thecompounds of the present disclosure are then added and IC₅₀ values aredetermined using an EGFR biochemical assay described above.

Solid high-binding ELISA plates are coated with goat anti-EGFR captureantibody. Plates are then blocked with BSA in a buffer, and then washed.Aliquots of lysed cell are added to each well of the ELISA plate and theplate is incubated. An anti-phospho-EGFR is then added and is followedby further incubation. After washing, anti-rabbit-HRP is added and theplate is again incubated. Chemiluminescent detection is carried out withSuperSignal ELISA Pico substrate. Signal is read on EnVision platereader using built-in UltraLUM setting.

Western Blotting

Cell lysates are equalized to protein content and loaded onto a gel withrunning buffer. Membranes are probed with primary antibodies and arethen washed. HRP-conjugated secondary antibodies are added and afterwashing. HRP is detected using a HRP substrate reagent and recorded withan imager.

Cell Proliferation Assays

Cell lines are plated in media. The compounds of the present disclosureare then serially diluted and transferred to the cells. Cell viabilityis measured via a luminescent readout. Data is analyzed by non-linearregression curve-fitting.

Methods of the Disclosure

In another aspect, the disclosure provides a method of inhibiting akinase, comprising contacting the kinase with a compound of disclosedherein, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof. In some embodiments, thekinase comprises a mutated cysteine residue. In further embodiments, themutated cysteine residue is located in or near the position equivalentto Cys 797 in EGFR, including such position in Jak3, Blk, Bmx, Btk, HER2(ErbB2), HER4 (ErbB4), Itk, Tec, and Txk. In other embodiments, themethod further comprises a second agent wherein said second agentprevents kinase dimer formation. In some embodiments, the second agentthat prevents kinase dimer formation is an antibody. In furtherembodiments, the second agent prevents EGFR dimer formation. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In another aspect, the disclosure provides a method of inhibiting akinase, comprising contacting the kinase with a compound of disclosedherein, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, and a second agent whereinsaid second agent prevents dimer formation of the kinase. In someembodiments, the kinase comprises a mutated cysteine residue. In furtherembodiments, the mutated cysteine residue is located in or near theposition equivalent to Cys 797 in EGFR, including such position in Jak3,Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk. In someembodiments, the second agent that prevents kinase dimer formation is anantibody. In further embodiments, the second agent prevents EGFR dimerformation. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

In another aspect, the disclosure provides a method of inhibiting akinase, the method comprising administering to a subject in need thereofan effective amount of a compound of disclosed herein, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In some embodiments, the kinase is aHer-kinase. In other embodiments, the method further comprisesadministering a second agent wherein said second agent prevents dimerformation of the kinase. In some embodiments, the second agent thatprevents kinase dimer formation is an antibody. In further embodiments,the second agent prevents EGFR dimer formation. In further embodiments,the second agent that prevents EGFR dimer formation is cetuximab,trastuzumab, or panitumumab. In further embodiments, the second agentthat prevents EGFR dimer formation is cetuximab.

In another aspect, the disclosure provides a method of inhibiting akinase, the method comprising administering to a subject in need thereofan effective amount of a compound of disclosed herein, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, and a second agent wherein saidsecond agent prevents dimer formation of the kinase. In someembodiments, the EGFR is a Her-kinase. In some embodiments, the secondagent that prevents kinase dimer formation is an antibody. In furtherembodiments, the second agent prevents EGFR dimer formation. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In still another aspect, the disclosure provides a method of inhibitingepidermal growth factor receptor (EGFR), the method comprisingadministering to a subject in need thereof an effective amount of acompound of disclosed herein, or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In someembodiments, the method further comprises administering a second agentwherein said second agent prevents EGFR dimer formation. In someembodiments, the second agent that prevents EGFR dimer formation is anantibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

In another aspect, the disclosure provides a method of inhibitingepidermal growth factor receptor (EGFR), the method comprisingadministering to a subject in need thereof an effective amount of acompound of disclosed herein, or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and asecond agent wherein said second agent prevents EGFR dimer formation. Insome embodiments, the second agent that prevents EGFR dimer formation isan antibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

Another aspect of the disclosure provides a method of treating orpreventing a disease, the method comprising administering to a subjectin need thereof an effective amount of a compound of disclosed herein,or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In some embodiments, the disease ismediated by a kinase. In further embodiments, the kinase comprises amutated cysteine residue. In further embodiments, the mutated cysteineresidue is located in or near the position equivalent to Cys 797 inEGFR, including such positions in Jak3, Blk, Bmx, Btk, HER2 (ErbB2),HER4 (ErbB4), Itk, Tec, and Txk. In some embodiments, the method furthercomprises administering a second agent wherein said second agentprevents dimer formation of the kinase. In some embodiments, the secondagent that prevents kinase dimer formation is an antibody. In furtherembodiments, the second agent prevents EGFR dimer formation. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In some embodiments, the disease is mediated by EGFR (e.g., EGFR plays arole in the initiation or development of the disease). In furtherembodiments, the EGFR is a Her-kinase. In further embodiments, theHer-kinase is HER1, HER2, or HER4.

In another aspect, the disclosure provides a method of treating orpreventing a disease, the method comprising administering to a subjectin need thereof an effective amount of a compound of disclosed herein,or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, and a second agent wherein saidsecond agent prevents dimer formation of a kinase. In some embodiments,the disease is mediated by a kinase. In further embodiments, the kinasecomprises a mutated cysteine residue. In further embodiments, themutated cysteine residue is located in or near the position equivalentto Cys 797 in EGFR, including such positions in Jak3, Blk, Bmx, Btk,HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk.

In other embodiments, the disease is mediated by EGFR (e.g., EGFR playsa role in the initiation or development of the disease). In furtherembodiments, the EGFR is a Her-kinase. In further embodiments, theHer-kinase is HER1, HER2, or HER4. In some embodiments, the second agentthat prevents EGFR dimer formation is an antibody. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In certain embodiments, the disease is cancer or a proliferationdisease.

In further embodiments, the disease is lung cancer, colon cancer, breastcancer, prostate cancer, liver cancer, pancreas cancer, brain cancer,kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer,gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma,hepatocellular carcinoma, papillary renal carcinoma, head and necksquamous cell carcinoma, leukemias, lymphomas, myelomas, or solidtumors.

In other embodiments, the disease is inflammation, arthritis, rheumatoidarthritis, spondyiarthropathies, gouty arthritis, osteoarthritis,juvenile arthritis, and other arthritic conditions, systemic lupuserthematosus (SLE), skin-related conditions, psoriasis, eczema, burns,dermatitis, neuroinflammation, allergy, pain, neuropathic pain, fever,pulmonary disorders, lung inflammation, adult respiratory distresssyndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonaryinflammatory disease, and chronic obstructive pulmonary disease (COPD),cardiovascular disease, arteriosclerosis, myocardial infarction(including post-myocardial infarction indications), thrombosis,congestive heart failure, cardiac reperfusion injury, as well ascomplications associated with hypertension and/or heart failure such asvascular organ damage, restenosis, cardiomyopathy, stroke includingischemic and hemorrhagic stroke, reperfusion injury, renal reperfusioninjury, ischemia including stroke and brain ischemia, and ischemiaresulting from cardiac/coronary bypass, neurodegenerative disorders,liver disease and nephritis, gastrointestinal conditions, inflammatorybowel disease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, ulcerative diseases, gastric ulcers, viral andbacterial infections, sepsis, septic shock, gram negative sepsis,malaria, meningitis, HIV infection, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, herpes virus, myalgias due to infection, influenza,autoimmune disease, graft vs. host reaction and allograft rejections,treatment of bone resorption diseases, osteoporosis, multiple sclerosis,cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bonecancer, epithelial call-derived neoplasia (epithelial carcinoma), basalcell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer,mouth cancer, esophageal cancer, small bowel cancer, stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovariancancer, cervical cancer, lung cancer, breast cancer, skin cancer,squamus cell and/or basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that affect epithelial cellsthroughout the body, chronic myelogenous leukemia (CML), acute myeloidleukemia (AML) and acute promyelocytic leukemia (APL), angiogenesisincluding neoplasia, metastasis, central nervous system disorders,central nervous system disorders having an inflammatory or apoptoticcomponent, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis, spinal cord injury, andperipheral neuropathy, or B-Cell Lymphoma.

In further embodiments, the disease is inflammation, arthritis,rheumatoid arthritis, spondylarthropathies, gouty arthritis,osteoarthritis, juvenile arthritis, and other arthritic conditions,systemic lupus erthematosus (SLE), skin-related conditions, psoriasis,eczema, dermatitis, pain, pulmonary disorders, lung inflammation, adultrespiratory distress syndrome, pulmonary sarcoisosis, asthma, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD), cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),congestive heart failure, cardiac reperfusion injury, inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome, leukemiaor lymphoma.

Another aspect of the disclosure provides a method of treating a kinasemediated disorder, the method comprising administering to a subject inneed thereof an effective amount of a compound of disclosed herein, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In other embodiments, the compound isan inhibitor of HER1, HER2, or HER4. In other embodiments, the subjectis administered an additional therapeutic agent. In other embodiments,the compound and the additional therapeutic agent are administeredsimultaneously or sequentially.

In another aspect, the disclosure provides a method of treating a kinasemediated disorder, the method comprising administering to a subject inneed thereof an effective amount of a compound of disclosed herein, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, and a second agent wherein saidsecond agent prevents EGFR dimer formation. In other embodiments, thecompound is an inhibitor of HER1, HER2, or HER4. In other embodiments,the subject is administered an additional therapeutic agent. In otherembodiments, the compound, the second agent that prevents EGFR dimerformation, and the additional therapeutic agent are administeredsimultaneously or sequentially. In some embodiments, the second agentthat prevents EGFR dimer formation is an antibody. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In other embodiments, the disease is cancer. In further embodiments, thecancer is lung cancer, colon cancer, breast cancer, prostate cancer,liver cancer, pancreas cancer, brain cancer, kidney cancer, ovariancancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breastcancer, pancreatic cancer, glioma, glioblastoma, hepatocellularcarcinoma, papillary renal carcinoma, head and neck squamous cellcarcinoma, leukemias, lymphomas, myelomas, or solid tumors.

In another aspect, the disclosure provides a method of treating orpreventing cancer, wherein the cancer cell comprise activated EGFR,comprising administering to a subject in need thereof an effectiveamount of a compound of disclosed herein, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In another aspect, the disclosure provides a method of treating orpreventing cancer, wherein the cancer cell comprise activated EGFR,comprising administering to a subject in need thereof an effectiveamount of a compound of disclosed herein, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof and a second agent wherein said second agent prevents EGFR dimerformation. In some embodiments, the second agent that prevents EGFRdimer formation is an antibody. In further embodiments, the second agentthat prevents EGFR dimer formation is cetuximab, trastuzumab, orpanitumumab. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab.

In certain embodiments, the EGFR activation is selected from mutation ofEGFR, amplification of EGFR, expression of EGFR, and ligand mediatedactivation of EGFR.

In further embodiments, the mutation of EGFR is located at G719S, G719C,G719A, L858R, L861Q, an exon 19 deletion mutation, or an exon 20insertion mutation.

Another aspect of the disclosure provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of EGFR inhibition for the treatment of cancer, comprisingadministering to the subject an effective amount of a compound ofdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of EGFR inhibition for the treatment of cancer, comprisingadministering to the subject an effective amount of a compound ofdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, and optionally asecond agent wherein said second agent prevents EGFR dimer formation. Insome embodiments, the second agent that prevents EGFR dimer formation isan antibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

In certain embodiments, the subject identified as being in need of EGFRinhibition is resistant to a known EGFR inhibitor, including but notlimited to, gefitinib or erlotinib. In certain embodiments, a diagnostictest is performed to determine if the subject has an activating mutationin EGFR. In certain embodiments, a diagnostic test is performed todetermine if the subject has an EGFR harboring an activating and a drugresistance mutation. Activating mutations comprise without limitationL858R, G719S, G719C, G719A, L718Q, L861Q, a deletion in exon 19 and/oran insertion in exon 20. Drug resistant EGFR mutants can have withoutlimitation a drug resistance mutation comprising T790M, T854A, L718Q,C797S, or D761Y. The diagnostic test can comprise sequencing,pyrosequencing, PCR, RT-PCR, or similar analysis techniques known tothose of skill in the art that can detect nucleotide sequences.

In another aspect, the disclosure provides a method of treating orpreventing cancer, wherein the cancer cell comprises an activated ERBB2,comprising administering to a subject in need thereof an effectiveamount of a compound of disclosed herein, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof. In certain embodiments, the ERBB2 activation is selected frommutation of ERBB2, expression of ERBB2 and amplification of ERBB2. Infurther embodiments, the mutation is a mutation in exon 20 of ERBB2.

In another aspect, the disclosure provides a method of treating orpreventing cancer, wherein the cancer cell comprises an activated ERBB2,comprising administering to a subject in need thereof an effectiveamount of a compound of disclosed herein, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, and a second agent wherein said second agent prevents ERBB2dimer formation. In certain embodiments, the ERBB2 activation isselected from mutation of ERBB2, expression of ERBB2 and amplificationof ERBB2. In further embodiments, the mutation is a mutation in exon 20of ERBB2. In some embodiments, the second agent that prevents ERBB2dimer formation is an antibody. In further embodiments, the second agentthat prevents ERBB2 dimer formation is cetuximab, trastuzumab, orpanitumumab. In further embodiments, the second agent that preventsERBB2 dimer formation is cetuximab.

In another aspect, the disclosure provides a method of treating cancerin a subject, wherein the subject is identified as being in need ofERBB2 inhibition for the treatment of cancer, comprising administeringto the subject in need thereof an effective amount of a compound ofdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of treating cancerin a subject, wherein the subject is identified as being in need ofERBB2 inhibition for the treatment of cancer, comprising administeringto the subject in need thereof an effective amount of a compound ofdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, and optionally asecond agent wherein said second agent prevents ERBB2 dimer formation.In some embodiments, the second agent that prevents ERBB2 dimerformation is an antibody. In further embodiments, the second agent thatprevents ERBB2 dimer formation is cetuximab, trastuzumab, orpanitumumab. In further embodiments, the second agent that preventsERBB2 dimer formation is cetuximab.

Another aspect of the disclosure provides a method of preventingresistance to a known EGFR inhibitor, including but not limited to,gefitinib or erlotinib in a disease, comprising administering to asubject in need thereof an effective amount of a compound of disclosedherein, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof.

Another aspect of the disclosure provides a method of preventingresistance to a known EGFR inhibitor, including but not limited to,gefitinib or erlotinib in a disease, comprising administering to asubject in need thereof an effective amount of a compound of disclosedherein, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, and a second agent whereinsaid second agent prevents EGFR dimer formation. In some embodiments,the second agent that prevents EGFR dimer formation is an antibody. Infurther embodiments, the second agent that prevents EGFR dimer formationis cetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

In certain embodiments, the disclosure provides a method of treating anyof the disorders described herein, wherein the subject is a human. Incertain embodiments, the disclosure provides a method of preventing anyof the disorders described herein, wherein the subject is a human.

In another aspect, the disclosure provides a compound of disclosedherein, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in the manufactureof a medicament for treating or preventing a disease in which EGFR playsa role.

In another aspect, the disclosure provides a compound of disclosedherein, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, and a second agent whereinsaid second agent prevents EGFR dimer formation for use in themanufacture of a medicament for treating or preventing a disease inwhich EGFR plays a role. In some embodiments, the second agent thatprevents EGFR dimer formation is an antibody. In further embodiments,the second agent that prevents EGFR dimer formation is cetuximab,trastuzumab, or panitumumab. In further embodiments, the second agentthat prevents EGFR dimer formation is cetuximab.

In still another aspect, the disclosure provides the use of a compoundof disclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment orprevention of a disease in which EGFR plays a role.

In another aspect, the disclosure provides the use of a compound ofdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, and a second agentwherein said second agent prevents EGFR dimer formation in the treatmentor prevention of a disease in which EGFR plays a role. In someembodiments, the second agent that prevents EGFR dimer formation is anantibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

As inhibitors of Her kinases, the compounds and compositions of thisdisclosure are particularly useful for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease, condition, or disorder. In one aspect, thepresent disclosure provides a method for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease state. In another aspect, the presentdisclosure provides a method for treating or lessening the severity of akinase disease, condition, or disorder where inhibition of enzymaticactivity is implicated in the treatment of the disease. In anotheraspect, this disclosure provides a method for treating or lessening theseverity of a disease, condition, or disorder with compounds thatinhibit enzymatic activity by binding to the protein kinase. Anotheraspect provides a method for treating or lessening the severity of akinase disease, condition, or disorder by inhibiting enzymatic activityof the kinase with a protein kinase inhibitor.

In some embodiments, said method is used to treat or prevent a conditionselected from autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, neurological and neurodegenerativediseases, cardiovascular diseases, hormone related diseases, allergies,asthma, and Alzheimer's disease. In other embodiments, said condition isselected from a proliferative disorder and a neurodegenerative disorder.

One aspect of this disclosure provides compounds that are useful for thetreatment of diseases, disorders, and conditions characterized byexcessive or abnormal cell proliferation. Such diseases include, but arenot limited to, a proliferative or hyperproliferative disease, and aneurodegenerative disease. Examples of proliferative andhyperproliferative diseases include, without limitation, cancer. Theterm “cancer” includes, but is not limited to, the following cancers:breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus;larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma;lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma,lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas,adenocarcinoma; thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladdercarcinoma; liver carcinoma and biliary passages; kidney carcinoma;myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine;colonrectum, large intestine, rectum, brain and central nervous system;chronic myeloid leukemia (CML), and leukemia. The term “cancer”includes, but is not limited to, the following cancers: myeloma,lymphoma, or a cancer selected from gastric, renal, or and the followingcancers: head and neck, oropharangeal, non-small cell lung cancer(NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, andpulmonary.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular), lung cancer (e.g., small-cell and non-small cell), breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subject compoundsinclude, but are not limited to, cancer of skeletal or smooth muscle,stomach cancer, cancer of the small intestine, rectum carcinoma, cancerof the salivary gland, endometrial cancer, adrenal cancer, anal cancer,rectal cancer, parathyroid cancer, and pituitary cancer.

Additional cancers that the compounds described herein may be useful inpreventing, treating and studying are, for example, colon carcinoma,familiary adenomatous polyposis carcinoma and hereditary non-polyposiscolorectal cancer, or melanoma. Further, cancers include, but are notlimited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma,tongue carcinoma, salivary gland carcinoma, gastric carcinoma,adenocarcinoma, thyroid cancer (medullary and papillary thyroidcarcinoma), renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the disclosure, thepresent disclosure provides for the use of one or more compounds of thedisclosure in the manufacture of a medicament for the treatment ofcancer, including without limitation the various types of cancerdisclosed herein.

In some embodiments, the compounds of this disclosure are useful fortreating cancer, such as colorectal, thyroid, breast, and lung cancer;and myeloproliferative disorders, such as polycythemia vera,thrombocythemia, myeloid metaplasia with myelofibrosis, chronicmyelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilicsyndrome, juvenile myelomonocytic leukemia, and systemic mast celldisease. In some embodiments, the compounds of this disclosure areuseful for treating hematopoietic disorders, in particular,acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML),acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

This disclosure further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may occur in skin,esophageal tissue, breast and cervical intra-epithelial tissue.

Examples of neurodegenerative diseases include, without limitation,Adrenoleukodystrophy (ALD), Alexander's disease, Alper's disease,Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig'sDisease), Ataxia telangiectasia, Batten disease (also known asSpielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiformencephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasaldegeneration, Creutzfeldt-Jakob disease, Familial fatal insomnia,Frontotemporal lobar degeneration, Huntington's disease, HIV-associateddementia, Kennedy's disease, Krabbe's disease, Lewy body dementia,Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, NiemannPick disease, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick'sdisease, Primary lateral sclerosis, Prion diseases, ProgressiveSupranuclear Palsy, Refsum's disease, Sandhoff disease, Schilder'sdisease, Subacute combined degeneration of spinal cord secondary toPernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten disease (also knownas Batten disease), Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, Tabes dorsalis, and Toxic encephalopathy.

Another aspect of this disclosure provides a method for the treatment orlessening the severity of a disease selected from a proliferative orhyperproliterative disease, or a neurodegenerative disease, comprisingadministering an effective amount of a compound, or a pharmaceuticallyacceptable composition comprising a compound, to a subject in needthereof. In other embodiments, the method further comprisesadministering a second agent wherein said second agent prevents EGFRdimer formation. In some embodiments, the second agent that preventsEGFR dimer formation is an antibody. In further embodiments, the secondagent that prevents EGFR dimer formation is cetuximab, trastuzumab, orpanitumumab. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab.

As inhibitors of Her kinases, the compounds and compositions of thisdisclosure are also useful in biological samples. One aspect of thedisclosure relates to inhibiting protein kinase activity in a biologicalsample, which method comprises contacting said biological sample with acompound of the disclosure or a composition comprising said compound.The term “biological sample”, as used herein, means an in vitro or an exvivo sample, including, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof. Inhibition of protein kinase activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, blood transfusion, organ-transplantation, and biological specimenstorage.

Another aspect of this disclosure relates to the study of Her kinases inbiological and pathological phenomena; the study of intracellular signaltransduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The activity of the compounds and compositions of the present disclosureas Her kinase inhibitors may be assayed in vitro, in vivo, or in a cellline. In vitro assays include assays that determine inhibition of eitherthe kinase activity or ATPase activity of the activated kinase.Alternate in vitro assays quantitate the ability of the inhibitor tobind to the protein kinase and may be measured either by radio labellingthe inhibitor prior to binding, isolating the inhibitor/kinase complexand determining the amount of radio label bound, or by running acompetition experiment where new inhibitors are incubated with thekinase bound to known radioligands. Detailed conditions for assaying acompound utilized in this disclosure as an inhibitor of various kinasesare set forth in the Examples below.

In accordance with the foregoing, the present disclosure furtherprovides a method for preventing or treating any of the diseases ordisorders described above in a subject in need of such treatment, whichmethod comprises administering to said subject a therapeuticallyeffective amount of a compound of the disclosure, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, and optionally a second agent wherein said second agentprevents EGFR dimer formation. For any of the above uses, the requireddosage will vary depending on the mode of administration, the particularcondition to be treated and the effect desired.

In other embodiments, the compound and the second agent that preventsEGFR dimer formation are administered simultaneously or sequentially.

Pharmaceutical Compositions

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound of disclosed herein, or a pharmaceuticallyacceptable ester, salt, or prodrug thereof, together with apharmaceutically acceptable carrier.

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound of disclosed herein, or a pharmaceuticallyacceptable ester, salt, or prodrug thereof, and a second agent whereinsaid second agent prevents EGFR dimer formation together with apharmaceutically acceptable carrier. In some embodiments, the secondagent that prevents EGFR dimer formation is an antibody. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab, trastuzumab, or panitumumab. In further embodiments, thesecond agent that prevents EGFR dimer formation is cetuximab.

Compounds of the disclosure can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present disclosure in free form or in a pharmaceutically acceptablesalt form in association and optionally a second agent wherein saidsecond agent prevents EGFR dimer formation with at least onepharmaceutically acceptable carrier or diluent can be manufactured in aconventional manner by mixing, granulating or coating methods. Forexample, oral compositions can be tablets or gelatin capsules comprisingthe active ingredient together with a) diluents, e.g., lactose,dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)lubricants, e.g., silica, talcum, stearic acid, its magnesium or calciumsalt and/or polyethyleneglycol; for tablets also c) binders, e.g.,magnesium aluminum silicate, starch paste, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose and orpolyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar,alginic acid or its sodium salt, or effervescent mixtures; and/or e)absorbents, colorants, flavors and sweeteners. Injectable compositionscan be aqueous isotonic solutions or suspensions, and suppositories canbe prepared from fatty emulsions or suspensions. The compositions may besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. In addition, they may also containother therapeutically valuable substances. Suitable formulations fortransdermal applications include an effective amount of a compound ofthe present disclosure with a carrier. A carrier can include absorbablepharmacologically acceptable solvents to assist passage through the skinof the host. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin. Matrix transdermal formulations may also beused. Suitable formulations for topical application, e.g., to the skinand eyes, are preferably aqueous solutions, ointments, creams or gelswell-known in the art. Such may contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

Compounds and compositions of the disclosure can be administered intherapeutically effective amounts in a combinational therapy with one ormore therapeutic agents (pharmaceutical combinations) or modalities,e.g., a second agent wherein said second agent prevents EGFR dimerformation, non-drug therapies, etc. For example, synergistic effects canoccur with agents that prevents EGFR dimer formation, otheranti-proliferative, anti-cancer, immunomodulatory or anti-inflammatorysubstances. Where the compounds of the disclosure are administered inconjunction with other therapies, dosages of the co-administeredcompounds will of course vary depending on the type of co-drug employed,on the specific drug employed, on the condition being treated and soforth.

Combination therapy includes the administration of the subject compoundsin further combination with one or more other biologically activeingredients (such as, but not limited to, a second agent wherein saidsecond agent prevents EGFR dimer formation, a second and differentantineoplastic agent) and non-drug therapies (such as, but not limitedto, surgery or radiation treatment). For instance, the compounds of thedisclosure can be used in combination with other pharmaceutically activecompounds, preferably compounds that are able to enhance the effect ofthe compounds of the disclosure. The compounds of the disclosure can beadministered simultaneously (as a single preparation or separatepreparation) or sequentially to the other drug therapy or treatmentmodality. In general, a combination therapy envisions administration oftwo or more drugs during a single cycle or course of therapy.

In one aspect of the disclosure, the compounds may be administered incombination with one or more agents that prevent EGFR dimer formation.In some embodiments, the second agent that prevents EGFR dimer formationis an antibody. In further embodiments, the second agent that preventsEGFR dimer formation is cetuximab, trastuzumab, or panitumumab. Infurther embodiments, the second agent that prevents EGFR dimer formationis cetuximab.

In another aspect of the disclosure, the compounds may be administeredin combination with one or more separate pharmaceutical agents, e.g., achemotherapeutic agent, an immunotherapeutic agent, or an adjunctivetherapeutic agent. In one embodiment, the chemotherapeutic agent reducesor inhibits the binding of ATP with EGFR (e.g., gefitinib, erlotinib,AZD9291, CO-1686 or WZ4002).

The pharmaceutical compositions of the present disclosure comprise atherapeutically effective amount of a compound of the present disclosureformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Thepharmaceutical compositions of this disclosure can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.In other embodiments, the composition further comprises administering asecond agent wherein said second agent prevents EGFR dimer formation. Insome embodiments, the second agent that prevents EGFR dimer formation isan antibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisdisclosure with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis disclosure include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this disclosure.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this disclosure, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisdisclosure, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present disclosure,disorders are treated or prevented in a subject, such as a human orother animal, by administering to the subject a therapeuticallyeffective amount of a compound of the disclosure, in such amounts andfor such time as is necessary to achieve the desired result. The term“therapeutically effective amount” of a compound of the disclosure, asused herein, means a sufficient amount of the compound so as to decreasethe symptoms of a disorder in a subject. As is well understood in themedical arts a therapeutically effective amount of a compound of thisdisclosure will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

In general, compounds of the disclosure will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g., humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered,e.g., in divided doses up to four times a day or in retard form.Suitable unit dosage forms for oral administration comprise from ca. 1to 50 mg active ingredient.

In certain embodiments, a therapeutic amount or dose of the compounds ofthe present disclosure may range from about 0.1 mg/Kg to about 500mg/Kg, alternatively from about 1 to about 50 mg/Kg. In general,treatment regimens according to the present disclosure compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this disclosure per day in singleor multiple doses. Therapeutic amounts or doses will also vary dependingon route of administration, as well as the possibility of co-usage withother agents.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this disclosure may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present disclosure will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The disclosure also provides for a pharmaceutical combinations, e.g., akit, comprising a) a first agent which is a compound of the disclosureas disclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g., a compound of the disclosure and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of the disclosure and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g., the administration of three or more activeingredients.

In certain embodiments, these compositions optionally further compriseone or more additional therapeutic agents. For example, an agent thatprevents EGFR dimer formation, chemotherapeutic agents or otherantiproliferative agents may be combined with the compounds of thisdisclosure to treat proliferative diseases and cancer.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylenepolyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes, oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate, agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The protein kinaseinhibitors or pharmaceutical salts thereof may be formulated intopharmaceutical compositions for administration to animals or humans.These pharmaceutical compositions, which comprise an amount of theprotein inhibitor effective to treat or prevent a proteinkinase-mediated condition and a pharmaceutically acceptable carrier, areother embodiments of the present disclosure.

In another aspect, the disclosure provides a kit comprising a compoundcapable of inhibiting kinase activity selected from one or morecompounds of disclosed herein, or pharmaceutically acceptable salts,hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, andinstructions for use in treating cancer. In certain embodiments, the kitfurther comprises components for performing a test to determine whethera subject has activating and/or drug resistance mutations in EGFR.

In another aspect, the disclosure provides a kit comprising a compoundcapable of inhibiting EGFR activity selected from a compound ofdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a kit comprising a compoundcapable of inhibiting kinase activity selected from one or morecompounds of disclosed herein, or pharmaceutically acceptable salts,hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, asecond agent wherein said second agent prevents EGFR dimer formation,and instructions for use in treating cancer. In certain embodiments, thekit further comprises components for performing a test to determinewhether a subject has activating and/or drug resistance mutations inEGFR. In some embodiments, the second agent that prevents EGFR dimerformation is an antibody. In further embodiments, the second agent thatprevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab.In further embodiments, the second agent that prevents EGFR dimerformation is cetuximab.

In another aspect, the disclosure provides a kit comprising a compoundcapable of inhibiting EGFR activity selected from a compound ofdisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof and second agentwherein said second agent prevents EGFR dimer formation. In someembodiments, the second agent that prevents EGFR dimer formation is anantibody. In further embodiments, the second agent that prevents EGFRdimer formation is cetuximab, trastuzumab, or panitumumab. In furtherembodiments, the second agent that prevents EGFR dimer formation iscetuximab.

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

EXAMPLES

Analytical Methods, Materials, and Instrumentation

All reactions were monitored by Waters LC/MS system (Waters 2998Photodiode Array Detector, Waters SQ detector 2, Waters 515 HPLC pump,Waters 2545 Binary Gradient Module, Waters System Fluidics Organizer andWaters 2767 Sample Manager) using SunFire™ C18 column (4.6×50 mm, 5 μmparticle size): solvent gradient=80% A at 0 min, 1% A at 5 min; solventA=0.035% TFA in Water; solvent B=0.035% TFA in MeOH; flow rate: 1.5mL/min (method A) and Waters Acquity UPLC/MS system (Waters PDA eXDetector, QDa Detector, Sample manager—FL, Binary Solvent Manager) usingAcquity UPLC® BEH C18 column (2.1×50 mm, 1.7 μm particle size): solventgradient=80% A at 0 min, 5% A at 2 min; solvent A=0.1% formic acid inWater; solvent B=0.1% formic acid in Acetonitrile; flow rate: 0.6 mL/min(method B). Reaction products were purified by flash columnchromatography using CombiFlash®Rf with Teledyne Isco RediSep®Rf HighPerformance Gold or Silicycle SiliaSep™ High Performance columns (4 g,12 g, 24 g, 40 g, or 80 g) and Waters HPLC system using SunFire™ PrepC18 column (19×100 mm, 5 μm particle size): solvent gradient=80% A at 0min, 5% A at 25 min; solvent A=0.035% TFA in Water; solvent B=0.035% TFAin MeOH; flow rate: 25 mL/min. The purity of all compounds was over 95%and was analyzed with Waters LC/MS system. ¹H NMR was obtained using a600 MHz Varian Inova-600 or 400 MHz Varian. Chemical shifts are reportedrelative to chloroform (6=7.24) or dimethyl sulfoxide (6=2.50) for ¹HNMR. Data are reported as (br=broad, s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet).

Abbreviations Used in the Following Examples and Elsewhere Herein are:

-   atm atmosphere-   br broad-   DIPEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   ESI electrospray ionization-   EtOAc ethyl acetate-   HCl hydrochloric acid-   h hour(s)-   HATU bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxide hexafluoro-phosphate-   HPLC high-performance liquid chromatography-   LCMS liquid chromatography-mass spectrometry-   m multiplet-   MeOH methanol-   MHz megahertz-   min minutes-   MS mass spectrometry-   NMR nuclear magnetic resonance-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   ppm parts per million-   THF tetrahydrofuran-   TLC thin layer chromatography-   Xphos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Example 1: Synthesis of(R)-2-(1-oxoisoindolin-2-yl)-2-phenyl-N-(pyridin-2-yl)acetamide (I-8)

Step 1. Methyl (R)-2-(1-oxoisoindolin-2-yl)-2-phenylacetate

To a solution of methyl (R)-2-amino-2-phenylacetate (5 g, 30.3 mmol) andphthalaldehyde (4.0 g, 30.3 mmol) in CHCl₃ (100 mL) was added aceticacid (0.17 mL, 3.0 mmol) and the resulting mixture was heated to 80° C.After stirring for 4 hr, the reaction mixture was diluted with water(700 mL) and the resulting precipitate was filtered off. The solid wasdried using a stream of nitrogen gas to provide methyl(R)-2-(1-oxoisoindolin-2-yl)-2-phenylacetate (6.5 g, 80%) as anoff-white solid.

Step 2. (R)-2-(1-oxoisoindolin-2-yl)-2-phenylacetic acid

To a solution of methyl (R)-2-(1-oxoisoindolin-2-yl)-2-phenylacetate(6.5 g, 24.3 mmol) in THF/MeOH/water (150 mL, 1:1:1) was added lithiumhydroxide monohydrate (5.1 g, 121.7 mmol). After stirring for 1 h, thesolvent was removed under reduced pressure and the resulting residue wasdiluted with ice water. The aqueous mixture was acidified withconcentrated HCl and the resulting suspension isolated via filtration.The solid was dried using a stream of nitrogen gas to provide(R)-2-(1-oxoisoindolin-2-yl)-2-phenylacetic acid (4.77 g, 78%) as anoff-white solid.

Step 3. (R)-2-(1-oxoisoindolin-2-yl)-2-phenyl-N-(pyridin-2-yl)acetamide(I-8)

To a solution of methyl (R)-2-(1-oxoisoindolin-2-yl)-2-phenylacetic acid(50 mg, 0.20 mmol), 2-aminopyridine (36 mg, 0.38 mmol) and HATU (200 mg,0.53 mmol) in N,N-dimethylformamide (2 mL) was added DIPEA (0.17 mL,0.96 mmol). After stirring for 6 hr, the reaction mixture was dilutedwith EtOAc and washed with water five times. The organic layer was thendried over sodium sulfate, filtered, concentrated under reduced pressureand purified by preparative high performance liquid chromatography(HPLC) to obtain(R)-2-(1-oxoisoindolin-2-yl)-2-phenyl-N-(pyridin-4-yl)acetamide (I-8, 25mg, 32%) as a white solid. HPLC method B: Rt=0.63 min; MS m/z: 344.15[M+1].

Example 2: Synthesis of(R)-2-(1-oxo-5-phenylisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide(I-105)

Step 1. Methyl (R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenylacetate

To a solution of methyl (R)-2-amino-2-phenylacetate (2.8 g, 13.9 mmol)and methyl 4-bromo-2-(bromomethyl)benzoate (3.9 g, 12.7 mmol) inN,N-dimethylformamide (120 mL) was added DIPEA (6.6 mL, 38.0 mmol) andthe resulting mixture was heated to 80° C. After stirring overnight, thereaction mixture was cooled down to room temperature and diluted withwater (700 mL). The precipitate was filtered off and dried using astream of nitrogen gas to obtain methyl(R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenylacetate (3.2 g, 70%) as anoff-white solid.

Step 2. (R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenylacetic acid

To a solution of methyl(R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenylacetate (3.2 g, 8.89 mmol)in THF/MeOH/water (150 mL, 1:1:1) was added lithium hydroxidemonohydrate (2.65 g, 63.3 mmol). After stirring for 1 h, the solvent wasremoved under reduced pressure and the resulting residue was dilutedwith ice water. The aqueous mixture was acidified with concentrated HCland the resulting suspension isolated via filtration. The solid wasdried using a stream of nitrogen gas to obtain(R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenylacetic acid (2.8 g, 92%) asan off-white solid.

Step 3.(R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide(2-1)

To a solution of methyl(R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenylacetic acid (2.0 g, 5.78mmol), thiazol-2-amine (1.1 g, 11.6 mmol), and HATU (4.4 g, 11.6 mmol)in N,N-dimethylformamide (30 mL) was added DIPEA (4.0 mL, 23.1 mmol).After stirring for 6 hr, the reaction mixture was diluted with EtOAc andwashed with water five times. The organic layer was dried over sodiumsulfate, filtered, concentrated under reduced pressure and purified bycolumn chromatography on silica gel (DCM:EtOAc=9:1 to 4:6) to obtain(R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide(2-1, 1.8 g, 73%) as an off-white solid.

Step 4.(R)-2-(1-oxo-5-phenylisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide(I-105)

A mixture of(R)-2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide(50 mg, 0.117 mmol), phenyl boronic acid (21 mg, 0.175 mmol) and 2 NSodium carbonate (0.18 mL, 0.351 mmol) in dioxane (1 mL) was degassedand heated to 100° C. PdCl₂(dppf)₂ (5 mg, 0.007 mmol) and Xphos (4.5 mg,0.011 mmol) were then added and the resulting reaction mixture wasstirred for 2 hr. The reaction mixture was then cooled down to roomtemperature and diluted with dichloromethane. The resulting mixture waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby preparative high performance liquid chromatography (HPLC) to provide(R)-2-(1-oxo-5-phenylisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide(I-105, 25 mg, 50%) as a white solid. HPLC method A: Rt=4.64 min; MSm/z: 426.38 [M+1]. ¹H NMR 400 MHz (DMSO-d₆) δ 12.71 (bs, NH), 7.86 (s,1H), 7.84-7.77 (m, 2H), 7.72-7.68 (m, 2H), 7.53-7.38 (m, 10H), 7.29 (d,J=3.5 Hz, 1H), 6.36 (s, 1H), 4.83 (d, J=17.5 Hz, 1H), 4.05 (d, J=17.6Hz, 1H).

Example 3: Synthesis of(R)-2-(1-oxo-5-(phenylamino)isoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide(I-93)

A mixture of(R)-2-(6-bromo-1-oxoisoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl) acetamide(2-1, 50 mg, 0.117 mmol), aniline (22 mg, 0.234 mmol) and potassiumcarbonate (49 mg, 0.351 mmol) in 2-butanol (1 mL) was degassed andheated to 100° C. Pd₂(dba)₃ (110 mg, 0.012 mmol) and Xphos (84 mg, 0.176mmol) were then added and the resulting reaction mixture was stirred for4 hr. The reaction mixture was then cooled down to room temperature anddiluted with dichloromethane. The resulting mixture was washed withwater and brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified bypreparative high performance liquid chromatography (HPLC) to provide(R)-2-(1-oxo-5-(phenylamino)isoindolin-2-yl)-2-phenyl-N-(thiazol-2-yl)acetamide (I-93, 15 mg, 29%) as an off-white solid. HPLC method A:Rt=4.43 min; MS m/z: 441.38 [M+1].

Example 4: Synthesis of5-bromo-N-(2,3-dihydroxypropyl)-2-(((R)-2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzamide(I-111)

Step 1. (R)-2-((4-bromo-3-(methoxycarbonyl)phenyl)amino)-2-phenylaceticacid

To a solution of (R)-2-amino-2-phenylacetic acid (972 mg, 6.43 mmol) andmethyl 2-bromo-5-fluorobenzoate (1 g, 4.29 mmol) inN,N-dimethylformamide (10 mL) was added potassium carbonate (1.8 g, 13.0mmol) and the resulting mixture was stirred at 100° C. for 6 hr. Thereaction mixture was then diluted with ice water and acidified byconcentrated HCl. The resulting precipitate was isolated via filtrationand dried using a stream of nitrogen gas to provide(R)-2-((4-bromo-3-(methoxycarbonyl)phenyl)amino)-2-phenylacetic acid(1.17 g, 75%) as an off-white solid.

Step 2. Methyl(R)-5-bromo-2-((2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzoate

To a solution of(R)-2-((4-bromo-3-(methoxycarbonyl)phenyl)amino)-2-phenylacetic acid(1.0 g, 2.75 mmol), thiazol-2-amine (860 mg, 8.58 mmol) and HATU (3.3 g,8.58 mmol) in N,N-dimethylformamide (20 mL) was added DIPEA (3.0 mL,17.2 mmol). After stirring for 6 hr, the reaction mixture was dilutedwith EtOAc and washed with water five times. The organic layer was driedover sodium sulfate, filtered, concentrated under reduced pressure andpurified by column chromatography on silica gel (DCM:EtOAc=9:1 to 3:7)to provide methyl(R)-5-bromo-2-((2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzoateas an off-white solid.

Step 3.(R)-5-bromo-2-((2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzoicacid

To a solution of methyl(R)-5-bromo-2-((2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzoate(500 mg, 1.12 mmol) in THF/MeOH/water (3 mL, 1:1:1) was added lithiumhydroxide monohydrate (235 mg, 5.60 mmol). After stirring for 1 h, thesolvent was removed under reduced pressure and the resulting residue wasdiluted with ice water. The aqueous mixture was acidified withconcentrated HCl and the resulting suspension isolated via filtration.The solid was dried using a stream of nitrogen gas to obtain(R)-5-bromo-2-((2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzoicacid (324 mg, 67%) as an off-white solid.

Step 4.(5-bromo-N-(2,3-dihydroxypropyl)-2-(((R)-2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzamide(I-111)

To a solution of(R)-5-bromo-2-((2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzoicacid (50 mg, 0.116 mmol), 3-aminopropane-1,2-diol (17 mg, 0.188 mmol)and HATU (96 mg, 0.252 mmol) in N,N-dimethylformamide (1 mL) was addedDIPEA (66 μL, 0.378 mmol). The resulting solution was stirred for 2 hr,diluted with EtOAc and washed with water five times. The organic layerwas dried over sodium sulfate, filtered, concentrated under reducedpressure and purified by preparative high performance liquidchromatography (HPLC) to obtain5-bromo-N-(2,3-dihydroxypropyl)-2-(((R)-2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)amino)benzamide(I-111, 37 mg, 64%) as an off-white solid. HPLC method A: Rt=3.74 min;MS m/z: 505.22 [M+1].

The following compounds in Table 1 were synthesized according to theprocedures outlined in Examples 1-4.

TABLE 1 Compound Number ¹H NMR and/or MS (m/z) data I-1 Method B: Rt =1.29 min, MS m/z: 371.23 [M + 1]. I-2 Method B: Rt = 1.34 min, MS m/z:371.23 [M + 1]. I-3 Method B: Rt = 1.36 min, MS m/z: 436.22 [M + 1]. I-4Method B: Rt = 1.32 min, MS m/z: 422.19 [M + 1]. I-5 Method B: Rt = 1.25min, MS m/z: 364.17 [M + 1]. I-6 Method B: Rt = 1.47 min, MS m/z: 418.17[M + 1]. I-7 Method B: Rt = 0.73 min, MS m/z: 344.15 [M + 1]. I-8 MethodB: Rt = 0.63 min, MS m/z: 344.15 [M + 1]. I-9 Method B: Rt = 1.00 min,MS m/z: 407.21 [M + 1]. I-10 Method B: Rt = 0.74 min, MS m/z: 506.26[M + 1]. I-11 Method B: Rt = 0.73 min, MS m/z: 478.28 [M + 1]. I-12Method B: Rt = 1.15 min, MS m/z: 395.15 [M + 1]. I-13 Method B: Rt =0.80 min, MS m/z: 365.12 [M + 1]. I-14 Method B: Rt = 0.68 min, MS m/z:520.30 [M + 1]; ¹H NMR 600 MHz (DMSO- d₆) δ 12.73 (s, NH), 8.11 (t, J =6.0 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.2Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.45 (t, J= 7.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.38 (s, 1H), 7.37 (d, J = 9.0Hz, 1H), 6.32 (s, 1H), 4.72 (d, J = 18.0 Hz, 1H), 3.98 (d, J = 17.4 Hz,1H), 3.95 (d, J = 15.6 Hz, 2H), 3.60 (t, J = 11.4 Hz, 2H), 3.39 (d, J =6.6 Hz, 2H), 3.10-3.07 (m, 2H), 3.05-2.99 (m, 2H), 1.89-1.83 (m, 2H).I-15 Method B: Rt = 0.64 min, MS m/z: 492.31 [M + 1]; ¹H NMR 600 MHz(DMSO- d₆) δ 12.75 (s, NH), 7.96 (t, J = 6.0 Hz, 1H), 7.81 (s, 1H), 7.72(d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.50 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.47-7.40 (m, 2H),7.38 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 4.72 (d, J = 17.4Hz, 1H), 3.97 (d, J = 17.4 Hz, 1H), 3.25 (q, J = 6.6 Hz, 2H), 3.04-3.01(m, 2H), 2.73 (s, 3H), 2.72 (s, 3H), 1.61-1.56 (m, 2H), 1.49 (quin, J =7.2 Hz, 2H). I-16 Method B: Rt = 0.65 min, MS m/z: 464.25 [M + 1]; ¹HNMR 600 MHz (DMSO- d₆) δ 12.72 (s, NH), 8.20 (t, J = 6.0 Hz, 1H) 7.88(s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 6.6 Hz, 1H), 7.56 (d, J= 7.8 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H),7.47-7.40 (m, 2H), 7.37 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H),4.72 (d, J = 18.0 Hz, 1H), 3.98 (d, J = 17.4 Hz, 1H), 3.57 (q, J = 6.2Hz, 2H), 3.21 (q, J = 5.4 Hz, 2H), 2.80 (s, 3H), 2.80 (s, 3H). I-17Method B: Rt = 0.96 min, MS m/z: 393.18 [M + 1]; ¹H NMR 600 MHz (DMSO-d₆) δ 12.74 (s, NH), 7.82 (s, 1H) 7.60 (t, J = 7.8 Hz, 1H), 7.55 (d, J =7.8 Hz, 1H), 7.52 (bs, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.47-7.44 (m, 1H),7.44 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.37(d, J = 8.4 Hz, 1H), 7.25 (s, 1H), 4.72 (d, J = 17.4 Hz, 1H), 3.97 (d, J= 17.4 Hz, 1H). I-18 Method B: Rt = 1.15 min, MS m/z: 395.15 [M + 1]; ¹HNMR 600 MHz (DMSO- d₆) δ 12.74 (s, NH), 8.26 (d, J = 8.4 Hz, 1H), 8.21(s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.73 (d, J= 6.6 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H, 7.50(t, J = 7.2 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H),6.37 (s, 1H), 4.72 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 12.0 Hz, 1H). I-19Method B: Rt = 0.89 min, MS m/z: 334.14 [M + 1]; ¹H NMR 400 MHz (DMSO-d₆) δ 11.77 (s, NH), 7.88 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.63-7.54(m, 2H), 7.54-7.38 (m, 6H), 7.11 (s, 1H), 6.20 (s, 1H), 4.72 (d, J =17.2 Hz, 1H), 3.92 (d, J = 17.6 Hz, 1H). I-20 Method B: Rt = 0.89 min,MS m/z: 334.10 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 11.77 (s, NH), 7.88(s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.63-7.54 (m, 2H), 7.54-7.38 (m, 6H),7.11 (s, 1H), 6.19 (s, 1H), 4.71 (d, J = 17.2 Hz, 1H), 3.92 (d, J = 18.0Hz, 1H). I-21 Method B: Rt = 1.16 min, MS m/z: 350.10 [M + 1]; ¹H NMR400 MHz (DMSO- d₆) δ 12.68 (s, NH), 7.74 (d, J = 8.0 Hz, 1H), 7.64-7.55(m, 2H), 7.53-7.42 (m, 5H), 7.39 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.28(d, J = 3.6 Hz, 1H), 6.31 (s, 1H), 4.76 (d, J = 17.6 Hz, 1H), 3.98 (d, J= 17.6 Hz, 1H). I-22 Method B: Rt = 1.05 min, MS m/z: 463.22 [M + 1]; ¹HNMR 400 MHz (DMSO- d₆) δ 12.87 (s, NH), 7.74 (d, J = 7.6 Hz, 1H), 7.69(s, 1H) 7.64-7.55 (m, 2H), 7.54-7.43 (m, 4H), 7.41-7.38 (m, 2H), 6.29(s, 1H), 4.73 (d, J = 17.6 Hz, 1H), 3.99 (d, J = 17.6 Hz, 1H), 3.53 (bs,4H), 3.32 (s, 4H). I-23 Method B: Rt = 0.70 min, MS m/z: 504.25 [M + 1].I-24 Method B: Rt = 0.69 min, MS m/z: 546.23 [M + 1]. I-25 Method B: Rt= 0.71 min, MS m/z: 476.27 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.87(s, NH), 7.80 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H) 7.62 (t, J = 7.3 Hz,1H), 7.58 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.50-7.43 (m,3H), 7.42-7.38 (m, 2H), 6.31 (s, 1H), 4.74 (d, J = 17.5 Hz, 1H), 4.60(bs, 2H), 3.98 (d, J = 17.6 H, 1H), 3.06 (bs, 2H), 2.82 (s, 3H). I-26Method B: Rt = 1.37 min, MS m/z: 395.23 [M + Na]. I-27 Method B: Rt =1.36 min, MS m/z: 423.09 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 11.56 (s,NH), 9.19 (s, 1H), 8.62 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H) 7.64-7.40 (m,8H), 6.37 (s, 1H), 4.77 (d, J = 17.3 Hz, 1H), 3.95 (d, J = 17.3 Hz, 1H).I-28 Method B: Rt = 1.49 min, MS m/z: 422.15 [M + 1]; ¹H NMR 400 MHz(DMSO- d₆) δ 11.29 (s, NH), 8.37 (s, 1H), 8.23 (d, J = 5.4 Hz, 1H), 7.74(d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H),7.51 (d, J = 7.1 Hz, 1H), 7.49-7.39 (m, 6H), 6.36 (s, 1H), 4.77 (d, J =17.6 Hz, 1H), 3.94 (d, J = 17.6 Hz, 1H). I-29 Method B: Rt = 1.48 min,MS m/z: 422.11 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 11.29 (s, NH), 8.37(s, 1H), 8.23 (d, J = 5.4 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.61 (t, J= 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 7.1 Hz, 1H),7.49-7.39 (m, 6H), 6.36 (s, 1H), 4.77 (d, J = 17.6 Hz, 1H), 3.94 (d, J =17.6 Hz, 1H). I-30 Method B: Rt = 1.25 min, MS m/z: 401.18 [M + 1]. I-31Method B: Rt = 1.12 min, MS m/z: 344.15 [M + 1]; ¹H NMR 400 MHz (DMSO-d₆) δ 11.03 (s, NH), 8.32 (d, J = 4.9 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H),7.81 (t, J = 8.1 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.60 (t, J = 7.7 Hz,1H), 7.57 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.49-7.38 (m,5H), 7.13 (dd, J = 6.6, 5.0 Hz, 1H), 6.38 (s, 1H), 4.80 (d, J = 17.6 Hz,1H), 3.94 (d, J = 17.6 Hz, 1H). I-32 Method B: Rt = 1.19 min, MS m/z:401.18 [M + 1]. I-33 Method B: Rt = 0.92 min, MS m/z: 385.18 [M + 1].I-34 Method B: Rt = 0.55 min, MS m/z: 333.15 [M + 1]. I-35 Method B: Rt= 0.54 min, MS m/z: 333.15 [M + 1]. I-36 Method B: Rt = 1.39 min, MSm/z: 428.10 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.99 (s, NH), 7.74 (d,J = 7.5 Hz, 1H), 7.65-7.55 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.49-7.42(m, 3H), 7.39 (s, 1H), 7.38-7.35 (m, 2H), 6.23 (s, 1H), 4.70 (d, J =17.6 Hz, 1H), 4.00 (d, J = 17.4 Hz, 1H). I-37 Method B: Rt = 0.78 min,MS m/z: 427.24 [M + 1]. I-38 Method B: Rt = 0.81 min, MS m/z: 365.12[M + 1]. I-39 Method B: Rt = 1.19 min, MS m/z: 364.17 [M + 1]; ¹H NMR400 MHz (DMSO- d₆) δ 12.61 (s, NH), 7.63 (d, J = 7.5 Hz, 1H), 7.60-7.56(m, 2H), 7.50 (d, J = 3.6 Hz, 1H), 7.48-7.43 (m, 1H), 7.36-7.33 (m, 2H),7.28-7.22 (m, 3H), 7.16 (t, J = 7.3 Hz, 1H), 5.47 (dd, J = 11.0, 4.9 Hz,1H), 4.72 (d, J = 17.5 Hz, 1H), 4.57 (d, J = 17.5 Hz, 1H), 3.43 (dd, J =14.4, 4.9 Hz, 1H), 3.26 (dd, J = 14.4, 11.1 Hz, 1H). I-40 Method B: Rt =1.47 min, MS m/z: 428.10 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.98 (s,NH), 7.74 (d, J = 7.5 Hz, 1H), 7.65-7.54 (m, 3H), 7.51 (t, J = 7.3 Hz,1H), 7.48-7.40 (m, 3H), 7.40-7.35 (m, 2H), 6.28 (s, 1H), 4.71 (d, J =17.5, 1H), 3.99 (d, J = 17.3 Hz, 1H). I-41 Method B: Rt = 0.98 min, MSm/z: 351.08 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 13.17 (s, NH), 9.22 (s,1H), 7.74 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.58 (t, J =8.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.49-7.42 (m, 3H), 7.41-7.38 (m,2H), 6.31 (s, 1H), 4.71 (d, J = 17.4, 1H), 4.00 (d, J = 17.5 Hz, 1H).I-42 Method B: Rt = 0.98 min, MS m/z: 351.08 [M + 1]; ¹H NMR 400 MHz(DMSO- d₆) δ 13.17 (s, NH), 9.22 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.62(t, J = 7.6 Hz, 1H), 7.58 (t, J = 8.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H),7.49-7.42 (m, 3H), 7.41-7.38 (m, 2H), 6.31 (s, 1H), 4.71 (d, J = 17.4,1H), 4.00 (d, J = 17.5 Hz, 1H). I-43 Method B: Rt = 0.78 min, MS m/z:477.30 [M + 1]. I-44 Method A: Rt = 3.00 min, MS m/z: 477.39 [M + 1].I-45 Method B: Rt = 1.19 min, MS m/z: 364.13 [M + 1]; ¹H NMR 400 MHz(DMSO- d₆) δ 12.61 (s, NH), 7.63 (d, J = 7.5 Hz, 1H), 7.60-7.56 (m, 2H),7.50 (d, J = 3.6 Hz, 1H), 7.48-7.43 (m, 1H), 7.36-7.33 (m, 2H),7.28-7.22 (m, 3H), 7.16 (t, J = 7.3 Hz, 1H), 5.47 (dd, J = 11.0, 4.9 Hz,1H), 4.72 (d, J = 17.5 Hz, 1H), 4.57 (d, J = 17.5 Hz, 1H), 3.43 (dd, J =14.4, 4.9 Hz, 1H), 3.26 (dd, J = 14.4, 11.1 Hz, 1H). I-46 Method B: Rt =1.50 min, MS m/z: 432.16 [M + 1]. I-47 Method B: Rt = 1.47 min, MS m/z:432.16 [M + 1]. I-48 Method B: Rt = 1.36 min, MS m/z: 436.22 [M + 1]; ¹HNMR 400 MHz (DMSO- d₆) δ 13.01 (s, NH), 8.09 (s, 1H), 7.63 (d, J = 7.5Hz, 1H), 7.58 (td, J = 6.5, 1.1 Hz, 2H), 7.48-7.43 (m, 1H), 7.32 (d, J =7.2 Hz, 2H), 7.24 (t, J = 7.2 Hz, 2H), 7.16 (tt, J = 7.3, 1.1 Hz, 1H),5.36 (dd, J = 11.0, 4.9 Hz, 1H), 4.58 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H),3.49-3.42 (m, 1H), 3.32-3.24 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). I-49Method B: Rt = 1.51 min, MS m/z: 442.63 [M + 1]; ¹H NMR 400 MHz (DMSO-d₆) δ 12.87 (s, NH), 7.63 (d, J = 7.5 Hz, 1H), 7.60-7.56 (m, 3H),7.48-7.43 (m, 1H), 7.31 (d, J = 7.2 Hz, 2H), 7.24 (t, J = 7.5 Hz, 2H),7.18-7.13 (m, 1H), 5.43 (dd, J = 10.9, 5.0 Hz, 1H), 4.60 (dd, J = 28.6,17.5 Hz, 2H), 3.42 (dd, J = 14.4, 5.0 Hz, 1H), 3.26 (dd, J = 14.4, 10.9Hz, 1H). I-50 Method B: Rt = 1.51 min, MS m/z: 442.63 [M + 1]; ¹H NMR400 MHz (DMSO- d₆) δ 12.87 (s, NH), 7.63 (d, J = 7.5 Hz, 1H), 7.61-7.56(m, 3H), 7.48-7.43 (m, 1H), 7.31 (d, J = 7.1 Hz, 2H), 7.24 (t, J = 7.5Hz, 2H), 7.18-7.14 (m, 1H), 5.43 (dd, J = 10.9, 5.0 Hz, 1H), 4.60 (dd, J= 28.6, 17.5 Hz, 2H), 3.42 (dd, J = 14.5, 5.1 Hz, 1H), 3.28 (dd, J =14.3, 10.9 Hz, 1H). I-51 Method A: Rt = 4.18 min, MS m/z: 343.48 [M +1]; ¹H NMR 400 MHz (DMSO- d₆) δ 10.50 (s, NH), 7.73 (d, J = 7.5 Hz, 1H),7.61-7.56 (m, 3H), 7.55 (t, J = 7.1 Hz, 1H), 7.49 (td, J = 7.0, 1.3 Hz,1H), 7.46-7.36 (m, 5H), 7.30 (t, J = 7.5 Hz, 2H), 7.06 (t, J = 7.4 Hz,1H), 6.20 (s, 1H), 4.81 (d, J = 17.7, 1H), 3.94 (d, J = 17.7 Hz, 1H).I-52 Method A: Rt = 4.15 min, MS m/z: 377.30 [M + 1]; ¹H NMR 400 MHz(DMSO- d₆) δ 10.13 (s, NH), 7.74 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 8.0,1.3 Hz, 1H), 7.58 (td, J = 7.6, 1.1 Hz, 1H), 7.55 (t, J = 7.1 Hz, 1H),7.51-7.46 (m, 2H), 7.46-7.42 (m, 4H), 7.41-7.36 (m, 1H), 7.33 (td, J =7.6, 1.4 Hz, 1H), 7.21 (td, J = 7.8, 1.6 Hz, 1H), 6.40 (s, 1H), 4.78 (d,J = 17.7, 1H), 3.96 (d, J = 17.7 Hz, 1H). I-53 Method A: Rt = 4.15 min,MS m/z: 379.28 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 10.34 (s, NH),7.79-7.71 (m, 2H), 7.58 (td, J = 7.6, 1.1 Hz, 1H), 7.54 (t, J = 7.2 Hz,1H), 7.48 (td, J = 7.5, 1.1 Hz, 1H), 7.46-7.36 (m, 5H), 7.34-7.28 (m,1H), 7.10-7.04 (m, 1H), 6.35 (s, 1H), 4.76 (d, J = 17.7, 1H), 3.93 (d, J= 17.7 Hz, 1H). I-54 Method A: Rt = 4.07 min, MS m/z: 371.29 [M + 1]; ¹HNMR 400 MHz (DMSO- d₆) δ 9.81 (s, NH), 7.74 (d, J = 7.5 Hz, 1H),7.60-7.39 (m, 8H), 7.08-7.01 (m, 3H), 6.23 (s, 1H), 4.76 (d, J = 17.7,1H), 3.95 (d, J = 17.7 Hz, 1H), 2.08 (s, 6H). I-55 Method A: Rt = 4.09min, MS m/z: 361.31 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 10.34 (s, NH),7.84-7.79 (m, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.58 (td, J = 7.6, 1.1 Hz,1H), 7.55 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.46-7.36 (m,5H), 7.28-7.20 (m, 1H), 7.20-7.14 (m, 2H), 6.40 (s, 1H), 4.78 (d, J =17.7, 1H), 3.93 (d, J = 17.7 Hz, 1H). I-56 Method A: Rt = 3.67 min, MSm/z: 362.34 [M + 1]. I-57 Method A: Rt = 3.75 min, MS m/z: 378.26 [M +1]; ¹H NMR 400 MHz (DMSO- d₆) δ 10.80 (s, NH), 8.40 (dd, J = 4.6, 1.2Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.58 (d, J= 7.4 Hz, 1H), 7.55 (t, J = 7.0 Hz, 1H), 7.50-7.36 (m, 6H), 7.33 (dd, J= 7.9, 4.7 Hz, 1H), 6.38 (s, 1H), 4.79 (d, J = 17.6, 1H), 3.93 (d, J =17.6 Hz, 1H). I-58 Method A: Rt = 4.12 min, MS m/z: 364.26 [M + 1]; ¹HNMR 400 MHz (DMSO- d₆) δ 7.74 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.6 Hz,1H), 7.57-7.53 (m, 1H), 7.52-7.44 (m, 4H), 7.43-7.39 (m, 2H), 7.35 (d, J= 3.5 Hz, 1H), 6.70 (s, 1H), 4.66 (d, J = 17.4, 1H), 3.85 (d, J = 17.4Hz, 1H), 3.53 (s, 3H). I-59 Method A: Rt = 4.60 min, MS m/z: 426.22 [M +1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.68 (s, NH), 7.93 (d, J = 1.8 Hz, 1H),7.90 (dd, J = 7.9, 1.8 Hz, 1H), 7.73-7.70 (m, 2H), 7.64 (d, J = 8.0 Hz,1H), 7.50-7.36 (m, 9H), 6.32 (s, 1H), 4.78 (d, J = 17.7, 1H), 4.01 (d, J= 17.7 Hz, 1H). I-60 Method A: Rt = 3.32 min, MS m/z: 427.31 [M + 1]; ¹HNMR 600 MHz (DMSO- d₆) δ 12.70 (bs, NH), 9.11 (d, J = 2.4 Hz, 1H), 8.72(dd, J = 1.2, 4.8 Hz, 1H), 8.49 (d, J = 6.6 Hz, 1H), 8.12 (d, J = 1.8Hz, 1H), 8.02 (dd, J = 1.8, 7.2 Hz, 1H), 7.76 (dd, J = 5.4, 8.4 Hz, 1H),7.72 (d, J = 7.8 Hz, 1H), 7.48-7.41 (m, 4H), 7.39 (s, 1H), 7.38 (d, J =7.8 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.32 (s, 1H), 4.82 (d, J = 18.0Hz, 1H), 4.04 (d, J = 18.6 Hz, 1H). I-61 Method A: Rt = 3.05 min, MSm/z: 427.24 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.70 (bs, NH), 8.85(d, J = 4.4 Hz, 2H), 8.27 (d, J = 1.3 Hz, 1H), 8.23 (d, J = 6.1 Hz, 2H),8.17 (dd, J = 8.0, 1.8 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.79 (d, J =8.0 Hz, 1H), 7.50-7.42 (m, 4H), 7.41-7.36 (m, 2H), 7.27 (d, J = 3.6 Hz,1H), 6.32 (s, 1H), 4.84 (d, J = 18.2 Hz, 1H), 4.08 (d, J = 18.2 Hz, 1H).I-62 Method A: Rt = 3.73 min, MS m/z: 428.20 [M + 1]. I-63 Method A: Rt= 4.10 min, MS m/z: 444.25 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.67(bs, NH), 8.32 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.80(dd, J = 7.9, 6.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 3.5Hz, 1H), 7.46-7.39 (m, 3H), 7.38-7.35 (m, 2H), 7.26 (d, J = 3.5 Hz, 1H),6.30 (s, 1H), 4.72 (d, J = 17.5 Hz, 1H), 4.13 (q, J = 7.3 Hz, 2H), 3.94(d, J = 17.6 Hz, 1H), 1.40 (t, J = 7.3 Hz, 3H). I-64 Method B: Rt = 0.98min, MS m/z: 416.16 [M + 1]. I-65 Method A: Rt = 4.67 min, MS m/z:484.30 [M + 1]; ¹H NMR 600 MHz (DMSO- d₆) δ 12.68 (bs, NH), 7.84 (m,1H), 7.82 (dd, J = 7.9, 1.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.48 (d,J = 3.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.43-7.39(m, 1H), 7.38-7.36 (m, 2H), 7.26 (d, J = 3.5 Hz, 1H), 7.19 (t, J = 2.1Hz, 1H), 7.18 (dd, J = 8.3, 2.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.30(s, 1H), 4.75 (d, J = 17.6 Hz, 1H), 4.26 (s, 4H), 3.98 (d, J = 17.7 Hz,1H). I-66 Method B: Rt = 1.41 min, MS m/z: 465.23 [M + 1]; ¹H NMR 600MHz (DMSO- d₆) δ 12.69 (s, NH), 11.16 (s, NH), 7.91 (s, 1H), 7.90 (dd, J= 7.9, 1.5 Hz, 1H), 7.86 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.49-7.44(m, 4H), 7.43-7.40 (m, 2H), 7.39-7.36 (m, 3H), 7.26 (d, J = 3.4 Hz, 1H),6.49-6.47 (m, 1H), 6.32 (s, 1H), 4.77 (d, J = 17.4 Hz, 1H), 3.99 (d, J =17.4 Hz, 1H). I-67 Method B: Rt = 1.47 min, MS m/z: 465.23 [M + 1]. I-68Method B: Rt = 0.84 min, MS m/z: 510.28 [M + 1]; ¹H NMR 600 MHz (DMSO-d₆) δ 12.69 (bs, NH), 7.89 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 8.0, 1.7Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.49-7.45(m, 3H), 7.44-7.40 (m, 1H), 7.39-7.36 (m, 2H), 7.27 (d, J = 3.5 Hz, 1H),7.09 (d, J = 8.9 Hz, 2H), 6.31 (s, 1H), 4.76 (d, J = 17.5 Hz, 1H), 3.99(d, J = 17.6 Hz, 1H), 3.42-3.39 (m, 4H), 3.25 (s, 4H). I-69 Method B: Rt= 0.84 min, MS m/z: 524.32 [M + 1]. I-70 Method A: Rt = 4.17 min, MSm/z: 477.26 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.70 (bs, NH), 9.38(d, J = 2.3 Hz, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 1.4 Hz, 1H),8.15 (dd, J = 8.0, 1.7 Hz, 1H), 8.11 (dd, J = 12.9, 7.6 Hz, 2H),7.86-7.81 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.73-7.68 (m, 1H),7.50-7.38 (m, 6H), 7.27 (d, J = 3.6 Hz, 1H), 6.35 (s, 1H), 4.84 (d, J =17.9 Hz, 1H), 4.07 (d, J = 17.9 Hz, 1H). I-71 Method A: Rt = 4.09 min,MS m/z: 477.26 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.69 (bs, NH), 8.90(dd, J = 4.2, 1.8 Hz, 1H), 8.47 (dd, J = 8.3, 1.7 Hz, 1H), 8.04 (dd, J =8.2, 1.3 Hz, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.86 (dd, J = 7.8, 1.6 Hz,1H), 7.83 (dd, J = 7.2, 1.4 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.65 (d,J = 7.9 Hz, 1H), 7.59 (dd, J = 8.3, 4.2 Hz, 1H), 7.50-7.38 (m, 5H), 7.27(d, J = 3.6 Hz, 1H), 6.33 (s, 1H), 4.82 (d, J = 17.6 Hz, 1H), 4.06 (d, J= 17.7 Hz, 1H). I-72 Method A: Rt = 4.60 min, MS m/z: 484.30 [M + 1]; ¹HNMR 400 MHz (DMSO- d₆) δ 12.69 (bs, NH), 8.06-8.02 (m, 3H), 7.98 (dd, J= 8.0, 1.7 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H),7.48 (d, J = 3.5 Hz, 1H), 7.47-7.36 (m, 5H), 7.27 (d, J = 3.6 Hz, 1H),6.32 (s, 1H), 4.81 (d, J = 17.8 Hz, 1H), 4.03 (d, J = 17.9 Hz, 1H), 3.39(s, 3H). I-73 Method B: Rt = 1.05 min, MS m/z: 441.23 [M + 1]. I-74Method A: Rt = 4.90 min, MS m/z: 510.33 [M + 1]; ¹H NMR 400 MHz (DMSO-d₆) δ 12.68 (bs, NH), 7.97 (d, J = 1.3 Hz, 1H), 7.92 (dd, J = 7.9, 1.8Hz, 1H), 7.86 (dt, J = 8.8, 2.1 Hz, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.48(d, J = 3.5 Hz, 1H), 7.47-7.36 (m, 7H), 7.26 (d, J = 3.5 Hz, 1H), 6.32(s, 1H), 4.79 (d, J = 17.7 Hz, 1H), 4.01 (d, J = 17.8 Hz, 1H). I-75Method A: Rt = 4.62 min, MS m/z: 444.32 [M + 1]; ¹H NMR 400 MHz (DMSO-d₆) δ 12.76 (bs, NH), 7.91 (s, 1H), 7.85 (dt, J = 7.9, 1.5 Hz, 1H), 7.75(d, J = 8.0 Hz, 1H), 7.66 (td, J = 7.9, 1.7 Hz, 1H), 7.56 (d, J = 3.5Hz, 1H), 7.55-7.37 (m, 8H), 7.34 (d, J = 3.6 Hz, 1H), 6.39 (s, 1H), 4.88(d, J = 17.7 Hz, 1H), 4.11 (d, J = 17.8 Hz, 1H). I-76 Method A: Rt =4.67 min, MS m/z: 444.38 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.68 (bs,NH), 7.98 (d, J = 1.2 Hz, 1H), 7.94 (dd, J = 7.9, 1.7 Hz, 1H), 7.65 (d,J = 8.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.54-7.36 (m, 7H), 7.27 (d, J = 3.5Hz, 1H), 7.21 (d, J = 8.1, 1.8 Hz, 1H), 6.33 (s, 1H), 4.79 (d, J = 17.7Hz, 1H), 4.02 (d, J = 17.8 Hz, 1H). I-77 Method A: Rt = 4.64 min, MSm/z: 444.32 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.68 (bs, NH), 7.92(d, J = 1.3 Hz, 1H), 7.88 (dd, J = 7.9, 1.7 Hz, 1H), 7.79-7.74 (m, 2H),7.64 (d, J = 8.0 Hz, 1H), 7.49-7.41 (m, 4H), 7.39-7.36 (m, 2H),7.33-7.25 (m, 3H), 6.31 (s, 1H), 4.78 (d, J = 17.7 Hz, 1H), 4.01 (d, J =17.7 Hz, 1H). I-78 Method A: Rt = 4.27 min, MS m/z: 470.35 [M + 1]; ¹HNMR 400 MHz (DMSO- d₆) δ 12.95 (bs, OH), 12.69 (bs, NH), 8.04-8.00 (m,3H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.68 (d,J = 8.0 Hz, 1H), 7.49-7.41 (m, 4H), 7.40-7.36 (m, 2H), 7.26 (d, J = 3.6Hz, 1H), 6.32 (s, 1H), 4.80 (d, J = 17.7 Hz, 1H), 4.03 (d, J = 17.7 Hz,1H). I-79 Method A: Rt = 4.67 min, MS m/z: 486.34 [M + 1]; ¹H NMR 600MHz (DMSO- d₆) δ 12.68 (bs, NH), 7.94 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H),7.62 (dd, J = 7.6, 2.6 Hz, 1H), 7.49-7.40 (m, 4H), 7.40-7.36 (m, 2H),7.28-7.25 (m, 1H), 6.82 (s, 2H), 6.51 (s, 1H), 6.32 (s, 1H), 4.78 (d, J= 17.6 Hz, 1H), 4.01 (d, J = 17.6 Hz, 1H), 3.80 (s, 3H), 3.80 (s, 3H).I-80 Method A: Rt = 4.62 min, MS m/z: 486.34 [M + 1]; ¹H NMR 600 MHz(DMSO- d₆) δ 12.68 (bs, NH), 7.72 (d, J = 1.1 Hz, 1H), 7.63 (dd, J =7.9, 1.6 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H),7.47-7.44 (m, 2H), 7.43-7.40 (m, 1H), 7.38-7.36 (m, 2H), 7.26 (d, J =3.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H), 4.74 (d, J = 17.5Hz, 1H), 3.98 (d, J = 17.5 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H). I-81Method A: Rt = 3.25 min, MS m/z: 540.47 [M + 1]; ¹H NMR 400 MHz (DMSO-d₆) δ 12.69 (bs, NH), 8.74 (t, J = 5.6 Hz, 1H), 8.03 (d, J = 1.2 Hz,1H), 8.00-7.95 (m, 3H), 7.88 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.1 Hz,1H), 7.50-7.36 (m, 6H), 7.27 (d, J = 3.6 Hz, 1H), 6.32 (s, 1H), 4.80 (d,J = 17.8 Hz, 1H), 4.03 (d, J = 17.9 Hz, 1H), 3.61 (q, J = 5.9 Hz, 2H),3.27 (q, J = 5.6 Hz, 2H), 2.85 (s, 3H), 2.84 (s, 2H). I-82 Method A: Rt= 3.29 min, MS m/z: 568.50 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.69(bs, NH), 8.57 (t, J = 5.7 Hz, 1H), 8.01 (d, J = 1.3 Hz, 1H), 7.98-7.93(m, 3H), 7.83 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.49-7.36(m, 6H), 7.27 (d, J = 3.6 Hz, 1H), 6.32 (s, 1H), 4.80 (d, J = 17.9 Hz,1H), 4.03 (d, J = 17.9 Hz, 1H), 3.30 (q, J = 6.0 Hz, 2H), 3.10-3.04 (m,2H), 2.76 (s, 3H), 2.75 (s, 2H), 1.70-1.60 (m, 2H), 1.55 (quint, J = 6.8Hz, 2H). I-83 Method A: Rt = 3.25 min, MS m/z: 582.45 [M + 1]; ¹H NMR400 MHz (DMSO- d₆) δ 12.69 (bs, NH), 8.78 (t, J = 5.8 Hz, 1H), 8.03 (d,J = 1.1 Hz, 1H), 8.00-7.95 (m, 3H), 7.88 (d, J = 8.5 Hz, 2H), 7.68 (d, J= 8.0 Hz, 1H), 7.49-7.36 (m, 6H), 7.27 (d, J = 3.6 Hz, 1H), 6.32 (s,1H), 4.80 (d, J = 17.8 Hz, 1H), 4.03 (d, J = 17.9 Hz, 1H), 3.98 (bs,2H), 3.69-3.60 (m, 4H), 3.60-3.50 (m, 2H), 3.50-3.40 (m, 2H), 3.15 (bs,2H). I-84 Method A: Rt = 3.27 min, MS m/z: 596.46 [M + 1]; ¹H NMR 600MHz (DMSO- d₆) δ 12.69 (bs, NH), 8.70 (t, J = 5.7 Hz, 1H), 8.02 (d, J =1.3 Hz, 1H), 7.97 (dd, J = 8.0, 1.7 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H),7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.49-7.41 (m, 4H),7.39-7.36 (m, 2H), 7.27 (d, J = 3.5 Hz, 1H), 6.32 (s, 1H), 4.80 (d, J =17.6 Hz, 1H), 4.03 (d, J = 17.6 Hz, 1H), 3.97 (d, J = 12.1 Hz, 2H), 3.62(t, J = 12.2 Hz, 2H), 3.46-3.32 (m, 4H), 3.16 (t, J = 6.6 Hz, 2H),3.10-3.02 (m, 2H), 1.92 (quint, J = 8.1 Hz, 2H). I-85 Method A: Rt =4.02 min, MS m/z: 539.38 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.71 (bs,NH), 8.00 (d, J = 1.3 Hz, 1H), 7.96 (dd, J = 7.9, 1.8 Hz, 1H), 7.82 (d,J = 8.3 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H),7.50 (d, J = 3.6 Hz, 1H), 7.49-7.43 (m, 3H), 7.42-7.38 (m, 2H), 7.28 (d,J = 3.7 Hz, 1H), 6.32 (s, 1H), 4.81 (d, J = 17.8 Hz, 1H), 4.04 (d, J =17.8 Hz, 1H), 3.70-3.50 (m, 4H). I-86 Method A: Rt = 4.97 min, MS m/z:430.31 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.66 (bs, NH), 7.66-7.63(m, 2H), 7.50-7.39 (m, 5H), 7.37-7.33 (m, 2H), 7.26 (d, J = 3.5 Hz, 1H),6.28 (s, 1H), 6.25-6.21 (m, 1H), 4.71 (d, J = 17.5 Hz, 1H), 3.93 (d, J =17.6 Hz, 1H), 2.42-2.36 (m, 2H), 2.21-2.15 (m, 2H), 1.76-1.69 (m, 2H),1.63-1.56 (m, 2H). I-87 Method A: Rt = 4.00 min, MS m/z: 357.42 [M + 1];¹H NMR 400 MHz (DMSO- d₆) δ 8.93 (t, J = 5.9 Hz, NH), 7.72 (d, J = 7.5Hz, 1H), 7.59-7.51 (m, 2H), 7.47 (td, J = 7.5, 0.8 Hz, 1H), 7.42-7.26(m, 7H), 7.25-7.19 (m, 3H), 6.08 (s, 1H), 4.78 (d, J = 17.7 Hz, 1H),4.33 (d, J = 6.0 Hz, 2H), 3.92 (d, J = 17.7 Hz, 1H). I-88 Method A: Rt =3.30 min, MS m/z: 540.41 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.71 (bs,NH), 8.89 (t, J = 5.6 Hz, 1H), 8.23-8.21 (m, 1H), 8.09 (d, J = 1.2 Hz,1H), 7.99 (dd, J = 8.0, 1.7 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.90 (d,J = 7.8 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H),7.52-7.44 (m, 4H), 7.42-7.38 (m, 2H), 7.29 (d, J = 3.5 Hz, 1H), 6.34 (s,1H), 4.83 (d, J = 17.8 Hz, 1H), 4.05 (d, J = 17.8 Hz, 1H), 3.65 (q, J =5.9 Hz, 2H) 3.32-3.28 (m, 2H), 2.87 (s, 3H), 2.87 (s, 3H). I-89 MethodB: Rt = 0.87 min, MS m/z: 568.30 [M + 1]. I-90 Method A: Rt = 3.25 min,MS m/z: 582.45 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.71 (bs, NH), 8.93(t, J = 5.4 Hz, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.99 (dd, J = 7.9, 1.4Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.53-7.44 (m, 4H), 7.42-7.38(m, 2H), 7.29 (d, J = 3.5 Hz, 1H), 6.34 (s, 1H), 4.83 (d, J = 17.7 Hz,1H), 4.05 (d, J = 17.8 Hz, 1H), 4.00 (bs, 2H), 3.73-3.65 (m, 4H), 3.57(bs, 2H), 3.38 (bs, 2H), 3.17 (bs, 2H). I-91 Method A: Rt = 3.25 min, MSm/z: 596.46 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.71 (bs, NH), 8.84(t, J = 5.7 Hz, 1H), 8.21-8.19 (m, 1H), 8.10 (d, J = 1.4 Hz, 1H), 7.99(dd, J = 8.0, 1.7 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.9Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.52-7.44(m, 4H), 7.42-7.38 (m, 2H), 7.29 (d, J = 3.6 Hz, 1H), 6.34 (s, 1H), 4.82(d, J = 17.8 Hz, 1H), 4.05 (d, J = 17.8 Hz, 1H), 3.98 (d, J = 12.8 Hz,2H), 3.64 (t, J = 12.1 Hz, 2H), 3.49-3.35 (m, 4H), 3.22-3.14 (m, 2H),3.14-3.00 (m, 2H), 2.00-1.90 (m, 2H). I-92 Method A: Rt = 4.02 min, MSm/z: 539.38 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.71 (bs, NH), 8.00(s, 1H), 7.96 (dd, J = 7.9, 1.4 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.75(s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.52-7.38(m, 7H), 7.28 (d, J = 3.5 Hz, 1H), 6.34 (s, 1H), 4.81 (d, J = 17.8 Hz,1H), 4.04 (d, J = 17.8 Hz, 1H), 3.70-3.35 (m, 4H). I-93 Method A: Rt =4.43 min, MS m/z: 441.38 [M + 1]. I-94 Method A: Rt = 3.80 min, MS m/z:526.39 [M + 1]. I-95 Method A: Rt = 3.07 min, MS m/z: 524.41 [M + 1]; ¹HNMR 400 MHz (DMSO- d₆) δ 12.66 (bs, NH), 8.83 (s, NH), 7.59 (d, J = 8.3Hz, 1H), 7.49 (d, J = 3.6 Hz, 1H), 7.48-7.40 (m, 3H), 7.37-7.33 (m, 4H),7.28 (d, J = 3.5 Hz, 1H), 7.23 (d, J = 1.3 Hz, 1H), 7.17 (dd, J = 8.0,1.4 Hz, 1H), 7.13 (dd, J = 8.4, 1.9 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H),6.29 (s, 1H), 4.72 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 5.7 Hz, 2H), 3.89(d, J = 17.4 Hz, 1H), 3.40-3.36 (m, 2H), 3.13-3.03 (m, 2H), 2.07-1.96(m, 2H), 1.90-1.80 (m, 2H). I-96 Method A: Rt = 4.85 min, MS m/z: 547.38[M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.62 (bs, NH), 8.42 (bs, NH),7.51-7.36 (m, 9H), 7.35-7.30 (m, 3H), 7.27 (d, J = 3.5 Hz, 1H), 7.11 (d,J = 8.9 Hz, 2H), 6.99-6.95 (m, 3H), 6.92 (dd, J = 8.4, 1.7 Hz, 1H), 6.25(s, 1H), 5.07 (s, 2H), 4.64 (d, J = 17.3 Hz, 1H), 3.84 (d, J = 17.3 Hz,1H). I-97 Method A: Rt = 4.52 min, MS m/z: 459.35 [M + 1]; ¹H NMR 400MHz (DMSO- d₆) δ 12.65 (bs, NH), 8.88 (bs, NH), 7.59 (d, J = 8.3 Hz,1H), 7.49 (d, J = 3.6 Hz, 1H), 7.47-7.40 (m, 3H), 7.37-7.34 (m, 2H),7.14-7.08 (m, 1H), 6.99-6.91 (m, 2H), 6.69 (td, J = 8.5, 2.2 Hz, 1H),6.27 (s, 1H), 4.70 (d, J = 17.5 Hz, 1H), 3.91 (d, J = 17.4 Hz, 1H). I-98Method A: Rt = 4.45 min, MS m/z: 441.31 [M + 1]; ¹H NMR 600 MHz (DMSO-d₆) δ 12.65 (bs, NH), 8.37 (bs, NH), 7.47 (d, J = 3.5 Hz, 1H), 7.46-7.32(m, 7H), 7.27-7.23 (m, 4H), 7.08 (d, J = 7.6 Hz, 2H), 6.86 (t, J = 7.3Hz, 1H), 6.25 (s, 1H), 4.63 (d, J = 17.0 Hz, 1H), 3.85 (d, J = 17.0 Hz,1H). I-99 Method A: Rt = 4.55 min, MS m/z: 459.35 [M + 1]; ¹H NMR 400MHz (DMSO- d₆) δ 12.68 (bs, NH), 8.63 (bs, NH), 7.49 (d, J = 3.5 Hz,1H), 7.48-7.42 (m, 4H), 7.40-7.36 (m, 3H), 7.32 (dd, J = 8.2, 2.2 Hz,1H), 7.30-7.23 (m, 2H), 6.90 (dd, J = 8.1, 1.7 Hz, 1H), 6.82 (dt, J =11.8, 2.0 Hz, 1H), 6.34 (td, J = 8.4, 2.8 Hz, 1H), 6.29 (s, 1H), 4.68(d, J = 17.1 Hz, 1H), 3.90 (d, J = 17.2 Hz, 1H). I-100 Method A: Rt =3.22 min, MS m/z: 524.41 [M + 1]. I-101 Method A: Rt = 4.65 min, MS m/z:444.32 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.71 (bs, NH), 7.84 (d, J =8.0 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55 (td, J = 7.8,1.7 Hz, 1H), 7.50 (d, J = 3.5 Hz, 1H), 7.49-7.31 (m, 7H), 7.29 (d, J =3.6 Hz, 1H), 6.34 (s, 1H), 4.82 (d, J = 17.6 Hz, 1H), 4.05 (d, J = 17.6Hz, 1H). I-102 Method A: Rt = 3.09 min, MS m/z: 524.41 [M + 1]; ¹H NMR400 MHz (DMSO- d₆) δ 12.71 (bs, NH), 7.81 (s, 1H), 7.76 (s, 2H), 7.64(d, J = 8.8 Hz, 2H), 7.50 (d, J = 3.5 Hz, 1H), 7.47 (d, J = 7.4 Hz, 2H),7.46-7.41 (m, 1H), 7.41-7.37 (m, 2H), 7.28 (d, J = 3.6 Hz, 1H), 7.12 (d,J = 8.9 Hz, 1H), 6.33 (s, 1H), 4.80 (d, J = 17.6 Hz, 1H), 4.01 (d, J =17.7 Hz, 1H), 3.96 (d, J = 13.9 Hz, 2H), 3.60-3.50 (m, 2H), 3.22-3.10(m, 2H), 3.03 (t, J = 12.5 Hz, 2H), 2.87 (s, 3H). I-103 Method A: Rt =4.62 min, MS m/z: 484.36 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.69 (bs,NH), 7.79-7.70 (m, 3H), 7.50 (d, J = 3.4 Hz, 1H), 7.47 (d, J = 7.4 Hz,2H), 7.46-7.42 (m, 1H), 7.40-7.36 (m, 2H), 7.28 (d, J = 3.4 Hz, 1H),7.21-7.16 (m, 2H), 6.96 (d, J = 8.2 Hz, 1H), 6.32 (s, 1H), 4.79 (d, J =17.5 Hz, 1H), 4.28 (s, 4H), 4.01 (d, J = 17.5 Hz, 1H). I-104 Method A:Rt = 4.37 min, MS m/z: 465.30 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.70(bs, NH), 11.20 (bs, NH), 7.86 (d, J = 10.8 Hz, 2H), 7.82-7.76 (m, 2H),7.56-7.37 (m, 9H), 7.29 (d, J = 3.5 Hz, 1H), 6.50 (t, J = 2.0 Hz, 1H),6.34 (s, 1H), 4.82 (d, J = 17.4 Hz, 1H), 4.04 (d, J = 17.5 Hz, 1H).I-105 Method A: Rt = 4.64 min, MS m/z: 426.38 [M + 1]; ¹H NMR 400 MHz(DMSO- d₆) δ 12.71 (bs, NH), 7.86 (s, 1H), 7.84-7.77 (m, 2H), 7.72-7.68(m, 2H), 7.53-7.38 (m, 10H), 7.29 (d, J = 3.5 Hz, 1H), 6.36 (s, 1H),4.83 (d, J = 17.5 Hz, 1H), 4.05 (d, J = 17.6 Hz, 1H). I-106 Method A: Rt= 4.74 min, MS m/z: 446.17 [M + 1]. I-107 Method A: Rt = 4.74 min, MSm/z: 446.15 [M + 1]. I-108 Method A: Rt = 3.65 min, MS m/z: 427.31 [M +1]. I-109 Method A: Rt = 4.45 min, MS m/z: 510.33 [M + 1]. I-110 MethodA: Rt = 3.13 min, MS m/z: 472.27 [M + 1]. I-111 Method A: Rt = 3.74 min,MS m/z: 505.22 [M + 1]. I-112 Method A: Rt = 4.47 min, MS m/z: 465.30[M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.68 (s, NH), 11.16 (s, NH), 7.91(s, 1H), 7.93-7.88 (m, 2H), 7.86 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H),7.49-7.36 (m, 9H), 7.27 (d, J = 3.5 Hz, 1H), 6.50-6.44 (m, 1H), 6.32 (s,1H), 4.78 (d, J = 17.5 Hz, 1H), 4.00 (d, J = 17.5 Hz, 1H). I-113 MethodA: Rt = 4.60 min, MS m/z: 444.32 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ12.68 (bs, NH), 7.83 (s, 1H), 7.78 (dt, J = 7.9, 1.5 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.58 (td, J = 7.8, 1.7 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H),7.48-7.29 (m, 8H), 7.27 (d, J = 3.6 Hz, 1H), 6.31 (s, 1H), 4.80 (d, J =17.8 Hz, 1H), 4.03 (d, J = 17.8 Hz, 1H). I-114 Method A: Rt = 4.37 min,MS m/z: 469.33 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.69 (bs, NH), 8.11(s, 1H), 8.05-7.98 (m, 3H), 7.83 (dd, J = 8.2, 1.2 Hz, 1H), 7.70 (d, J =8.0 Hz, 1H), 7.49-7.40 (m, 4H), 7.38 (d, J = 7.2 Hz, 2H), 7.27 (d, J =3.2 Hz, 1H), 6.32 (s, 1H), 4.81 (d, J = 17.9 Hz, 1H), 4.04 (d, J = 18.0Hz, 1H). I-115 Method A: Rt = 3.32 min, MS m/z: 510.46 [M + 1]. I-116Method A: Rt = 3.98 min, MS m/z: 403.32 [M + 1]; ¹H NMR 400 MHz (DMSO-d₆) δ 12.42 (bs, NH), 11.54 (bs, NH), 7.93 (dd, J = 7.9, 1.8 Hz, 1H),7.87 (dd, J = 4.5, 1.3 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.50-7.46 (m,2H), 7.42 (dd, J = 8.5, 1.7 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.22 (d,J = 3.6 Hz, 1H), 6.49 (t, J = 2.1 Hz, 1H), 5.08 (q, J = 7.3 Hz, 1H),4.69 (dd, J = 39.1, 17.4 Hz, 2H), 1.59 (d, J = 7.3 Hz, 3H). I-117 MethodA: Rt = 4.57 min, MS m/z: 548.40 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ12.41 (bs, NH), 7.87 (dd, J = 7.9, 1.86 Hz, 1H), 7.83 (s, 2H), 7.65 (d,J = 8.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 3.5 Hz, 1H),7.22 (d, J = 3.5 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 5.07 (q, J = 7.3 Hz,1H), 4.67 (dd, J = 39.1, 17.5 Hz, 2H), 3.49-3.43 (m, 4H), 3.18-3.14 (m,4H), 1.58 (d, J = 7.3 Hz, 3H), 1.41 (s, 9H). I-118 Method A: Rt = 2.87min, MS m/z: 448.41 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.41 (bs, NH),7.88 (d, J = 8.1 Hz, 1H), 7.85 (s, 2H), 7.69-7.63 (m, 3H), 7.47 (d, J =3.5 Hz, 1H), 7.22 (d, J = 3.5 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 5.06(q, J = 7.3 Hz, 1H), 4.68 (dd, J = 38.9, 17.5 Hz, 2H), 3.45-3.38 (m,4H), 3.24 (bs, 4H), 1.59 (d, J = 7.3 Hz, 3H). I-119 Method A: Rt = 4.97min, MS m/z: 628.46 [M + 1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.67 (bs, NH),7.77 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.48(d, J = 3.6 Hz, 1H), 7.47-7.36 (m, 6H), 7.26 (d, J = 3.6 Hz, 1H),6.90-6.87 (m, 1H), 6.87-6.85 (m, 1H), 6.30 (s, 1H), 4.77 (d, J = 17.7Hz, 1H), 4.00 (d, J = 17.7 Hz, 1H), 3.47-3.42 (m, 4H), 3.23-3.19 (m,4H), 1.41 (s, 9H). I-120 Method A: Rt = 3.37 min, MS m/z: 528.44 [M +1]; ¹H NMR 400 MHz (DMSO- d₆) δ 12.68 (bs, NH), 7.78 (s, 1H), 7.72 (dt,J = 8.0, 1.3 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50-7.35 (m, 7H), 7.26(d, J = 3.6 Hz, 1H), 6.99-6.90 (m, 2H), 6.30 (s, 1H), 4.77 (d, J = 17.7Hz, 1H), 4.00 (d, J = 17.8 Hz, 1H), 3.49-3.43 (m, 4H), 3.23 (bs, 4H).I-121 Method A: Rt = 3.13 min, MS m/z: 524.47 [M + 1]; ¹H NMR 400 MHz(DMSO- d₆) δ 12.69 (bs, NH), 7.97 (s, 1H), 7.92 (dd, J = 8.0, 1.7 Hz,1H), 7.79 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.51 (d, J =8.1 Hz, 2H), 7.49-7.40 (m, 4H), 7.39-7.36 (m, 2H), 6.31 (s, 1H), 4.79(d, J = 17.8 Hz, 1H), 4.01 (d, J = 17.8 Hz, 1H), 3.22 (bs, 4H), 2.94(bs, 4H). I-122 Method A: Rt = 4.55 min, MS m/z: 483.34 [M + 1]; ¹H NMR600 MHz (DMSO- d₆) δ 12.72 (bs, NH), 11.17 (bs, NH), 7.93-7.86 (s, 3H),7.62 (d, J = 8.0 Hz, 1H), 7.55-7.46 (m, 3H), 7.43 (d, J = 8.0 Hz, 1H),7.38 (s, 1H), 7.31-7.20 (m, 4H), 6.49 (s, 1H), 6.30 (s, 1H), 4.76 (d, J= 17.1 Hz, 1H), 4.12 (d, J = 17.3 Hz, 1H). I-123 Method B: Rt = 1.18min, MS m/z: 466.26 [M + 1]; ¹H NMR 600 MHz (DMSO- d₆) δ 12.72 (bs, NH),11.17 (bs, NH), 7.93-7.86 (s, 3H), 7.62 (d, J = 8.0 Hz, 1H), 7.55-7.46(m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.31-7.20 (m, 4H), 6.49(s, 1H), 6.30 (s, 1H), 4.76 (d, J = 17.1 Hz, 1H), 4.12 (d, J = 17.3 Hz,1H). I-124 Method B: Rt = 0.67 min, MS m/z: 511.27 [M + 1], ¹H NMR 600MHz (DMSO- d₆) δ 12.72 (bs, NH), 11.17 (bs, NH), 7.93-7.86 (s, 3H), 7.62(d, J = 8.0 Hz, 1H), 7.55-7.46 (m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 7.38(s, 1H), 7.31-7.20 (m, 4H), 6.49 (s, 1H), 6.30 (s, 1H), 4.76 (d, J =17.1 Hz, 1H), 4.12 (d, J = 17.3 Hz, 1H). I-125 Method B: Rt = 0.73 min,MS m/z: 542.27 [M + 1]; ¹H NMR 600 MHz (DMSO- d₆) δ 12.72 (bs, NH),11.17 (bs, NH), 7.93-7.86 (s, 3H), 7.62 (d, J = 8.0 Hz, 1H), 7.55-7.46(m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.31-7.20 (m, 4H), 6.49(s, 1H), 6.30 (s, 1H), 4.76 (d, J = 17.1 Hz, 1H), 4.12 (d, J = 17.3 Hz,1H). I-126 Method B: Rt = 0.63 min, MS m/z: 543.89 [M + 1]. ¹H NMR 500MHz (DMSO- d₆) δ 12.62 (bs, NH), 10.00 (bs, OH), 7.90-7.86 (m, 3H),7.69-7.65 (m, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 3.4 Hz, 1H),7.28 (d, J = 3.4 Hz, 1H), 7.15-7.09 (m, 3H), 6.94 (dd, J = 4.9, 8.9 Hz,1H), 6.87 (dd, J = 3.1, 9.2 Hz, 1H), 6.34 (s, 1H), 4.64 (d, J = 17.7 Hz,1H), 4.02 (d, J = 17.7 Hz, 1H), 3.46-3.42 (m, 4H), 3.27-3.23 (m, 4H),2.56 (bs, NH). I-127 Method B: Rt = 1.02 min, MS m/z: 465.97 [M + 1]. ¹HNMR 500 MHz (DMSO- d₆) δ 13.20 (s, NH), 11.19 (s, NH), 9.23 (s, 1H),7.95-7.91 (m, 3H), 7.63 (d, J = 7.9 Hz, 1H), 7.52-7.39 (m, 8H),6.52-6.50 (m, 1H), 6.35 (s, 1H), 4.95 (d, J = 17.4 Hz, 1H), 4.05 (d, J =17.4 Hz, 1H). I-128 Method B: Rt = 1.16 min, MS m/z: 464.99 [M + 1]. ¹HNMR 500 MHz (DMSO- d₆) δ 11.25 (bs, NH), 11.19 (bs, NH), 8.98 (s, 1H),8.64 (s, 1H), 7.96-7.88 (m, 3H), 7.63 (d, J = 7.9 Hz, 1H), 7.52-7.41 (m,7H), 7.40 (t, J = 2.6 Hz, 1H), 6.52-6.50 (m, 1H), 6.23 (s, 1H), 4.83 (d,J = 17.7 Hz, 1H), 4.03 (d, J = 17.7 Hz, 1H) I-129 Method B: Rt = 0.96min, MS m/z: 449.03 [M + 1]. ¹H NMR 500 MHz (DMSO- d₆) δ 11.80 (s, NH),11.19 (s, NH), 7.97-7.88 (m, 3H), 7.62 (d, J = 7.9 Hz, 1H), 7.57-7.41(m, 7H), 7.40 (t, J = 2.6 Hz, 1H), 6.52-6.50 (m, 1H), 6.23 (bs, 1H),4.75 (d, J = 17.4 Hz, 1H), 3.97 (d, J = 17.4 Hz, 1H). I-130 Method B: Rt= 1.11 min, MS m/z: 449.03 [M + 1]. ¹H NMR 500 MHz (DMSO- d₆) δ 11.19(s, NH), 10.88 (s, NH), 9.20 (s, 1H), 8.67 (s, 1H), 7.96-7.88 (m, 3H),7.63 (d, J = 7.9 Hz, 1H), 7.52-7.39 (m, 8H), 6.52-6.50 (m, 1H), 6.22 (s,1H), 4.79 (d, J = 17.4 Hz, 1H), 4.02 (d, J = 17.4 Hz, 1H). I-131 MethodB: Rt = 1.24 min, MS m/z: 478.98 [M + 1]. ¹H NMR 500 MHz (DMSO- d₆) δ12.62 (s, NH), 11.19 (s, NH), 7.95-7.88 (m, 3H), 7.63 (d, J = 7.9 Hz,1H), 7.52-7.38 (m, 8H), 6.83 (s, 1H), 6.52-6.50 (m, 1H), 6.31 (s, 1H),4.79 (d, J = 17.4 Hz, 1H), 4.02 (d, J = 17.4 Hz, 1H), 2.26 (s, 3H).I-132 Method B: Rt = 1.41 min, MS m/z: 532.89 [M + 1]. ¹H NMR 500 MHz(DMSO- d₆) δ 13.20 (s, NH), 11.19 (s, NH), 8.04 (s, 1H), 7.95-7.88 (m,3H), 7.63 (d, J = 8.5 Hz, 1H), 7.52-7.41 (m, 7H), 7.40 (t, J = 2.8 Hz,1H), 6.52-6.50 (m, 1H), 6.27 (s, 1H), 4.74 (d, J = 17.4 Hz, 1H), 4.06(d, J = 17.4 Hz, 1H). I-133 Method B: Rt = 0.65 min, MS m/z: 448.04 [M +1]. ¹H NMR 500 MHz (DMSO- d₆) δ 11.79 (bs, 2NH), 11.27 (s, NH),8.03-7.95 (m, 3H), 7.71 (d, J = 7.9 Hz, 1H), 7.60-7.47 (m, 8H), 6.85(bs, 2H), 6.60-6.58 (m, 1H), 6.33 (s, 1H), 4.93 (d, J = 17.7 Hz, 1H),4.09 (d, J = 17.7 Hz, 1H). I-134 Method B: Rt = 0.97 min, MS m/z: 460.06[M + 1]. ¹H NMR 500 MHz (DMSO- d₆) δ 11.19 (bs, NH), 10.99 (s, NH), 9.06(s, 2H), 8.94 (s, 1H), 7.96-7.88 (m, 3H), 7.63 (d, J = 7.9 Hz, 1H),7.52-7.42 (m, 7H), 7.40 (t, J = 2.8 Hz, 1H), 6.52-6.50 (m, 1H), 6.29 (s,1H), 4.82 (d, J = 17.7 Hz, 1H), 4.03 (d, J = 17.7 Hz, 1H). I-135 MethodB: Rt = 0.89 min, MS m/z: 561.90 [M + 1]; ¹H NMR 500 MHz (DMSO- d₆) δ12.61 (s, NH), 10.01 (s, OH), 7.78 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H),7.64 (d, J = 7.9 Hz, 1H), 7.53-7.47 (m, 2H), 7.27 (d, J = 3.7 Hz, 1H),7.12 (td, J = 8.5, 3.1 Hz, 1H), 7.01-6.90 (m, 3H), 6.87 (dd, J = 9.5,3.4 Hz, 1H), 6.32 (s, 1H), 4.65 (d, J = 17.7 Hz, 1H), 4.02 (d, J = 17.7Hz, 1H), 3.51-3.44 (m, 4H), 3.27-3.20 (m, 4H). I-136 Method B: Rt = 1.11min, MS m/z: 49.90 [M + 1]. I-137 Method B: Rt = 1.05 min, MS m/z:499.94 [M + 1]; ¹H NMR 500 MHz (DMSO- d₆) δ 12.62 (s, NH), 11.75 (s,NH), 9.97 (s, OH), 8.56 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H),8.00-7.95 (m, 2H), 7.67 (d J = 7.9 Hz, 1H), 7.53 (t, J = 2.9 Hz, 1H),7.49 (d, J = 3.7 Hz, 1H), 7.27 (d, J = 3.7 Hz, 1H), 7.12 (td, J = 8.5,3.1 Hz, 1H), 6.92 (dd, J = 8.9, 4.9 Hz, 1H), 6.88 (dd, J = 9.2, 3.1 Hz,1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 6.35 (s, 1H), 4.67 (d, J = 17.4 Hz,1H), 4.04 (d, J = 17.7 Hz, 1H). I-138 Method B: Rt = 0.94 min, MS m/z:545.94 [M + 1]; ¹H NMR 500 MHz (DMSO- d₆) δ 7.90-7.86 (m, 2H), 7.63-7.59(m, 3H), 7.49 (d, J = 3.7 Hz, 1H), 7.44-7.35 (m, 2H), 7.27 (d, J = 3.4Hz, 1H), 7.21-7.16 (m, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.45 (s, 1H), 4.75(d, J = 17.1 Hz, 1H), 4.15 (d, J = 17.4 Hz, 1H), 3.16-3.12 (m, 4H),2.92-2.86 (m, 4H). I-139 Method B: Rt = 0.98 min, MS m/z: 563.95 [M +1]; ¹H NMR 500 MHz (DMSO- d₆) δ 7.79 (s, 1H), 7.75 (dt, J = 7.9, 1.5 Hz,1H), 7.64 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 3.7 Hz, 1H), 7.46-7.34 (m,3H), 7.28 (d, J = 3.7 Hz, 1H), 7.21-7.16 (m, 1H), 6.88-6.83 (m, 2H),6.44 (s, 1H), 4.76 (d, J = 17.4 Hz, 1H), 4.17 (d, J = 17.4 Hz, 1H),3.20-3.14 (m, 4H), 2.90-2.83 (m, 4H). I-140 Method B: Rt = 1.37 min, MSm/z: 500.89 [M + 1]; ¹H NMR 500 MHz (DMSO- d₆) δ 12.76 (s, NH), 11.18(s, NH), 7.96-7.92 (m, 2H), 7.89 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H),7.64-7.48 (m, 2H), 7.47-7.36 (m, 4H), 7.31 (s, 1H), 7.22-7.17 (m, 1H),6.50 (bs, 1H), 6.47 (s, 1H), 4.76 (d, J = 17.1 Hz, 1H), 4.17 (d, J =17.1 Hz, 1H). I-141 Method B: Rt = 1.21 min, MS m/z: 501.91 [M + 1]; ¹HNMR 500 MHz (DMSO- d₆) δ 13.15 (s, NH), 12.77 (bs, NH), 8.00-7.96 (m,2H), 7.73 (dd, J = 8.9, 1.5 Hz, 1H), 7.69-7.63 (m, 2H), 7.50 (d, J = 3.1Hz, 1H), 7.45-7.36 (m, 2H), 7.29 (bs, 1H), 7.22-7.16 (m, 1H), 6.47 (s,1H), 4.79 (d, J = 17.4 Hz, 1H), 4.18 (d, J = 17.4 Hz, 1H). I-142 MethodB: Rt = 1.17 min, MS m/z: 501.87 [M + 1]; ¹H NMR 500 MHz (DMSO- d₆) δ12.70 (s, NH), 11.68 (s, NH), 8.50 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.1Hz, 1H), 7.94 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.6 Hz,1H), 7.47 (t, J = 2.9 Hz, 1H), 7.44 (d, J = 3.7 Hz, 1H), 7.39-7.31 (m,2H), 7.24 (d, J = 3.1 Hz, 1H), 7.16-7.11 (m, 1H), 6.45 (bs, 1H), 6.41(s, 1H), 4.71 (d, J = 17.4 Hz, 1H), 4.13 (d, J = 17.1 Hz, 1H).

Example 5: Synthesis of(R)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindolin-2-yl)-N-(thiazol-2-yl)acetamide

Step 1: Synthesis of methyl(R)-2-amino-2-(5-fluoro-2-hydroxyphenyl)acetate hydrochloride

To a solution of (R)-2-amino-2-(5-fluoro-2-hydroxyphenyl)acetic acid(500 mg, 2.26 mmol) in methanol (10 mL) was added thionyl chloride (0.33mL, 4.51 mmol) dropwise at 0° C. The resulting mixture was stirred for 1hr. After completion, the reaction mixture was concentrated underreduced pressure. The crude product was used in next step withoutfurther purification.

Step 2: Synthesis of methyl(R)-2-(6-bromo-1-oxoisoindolin-2-yl)-2-(5-fluoro-2-hydroxyphenyl)acetate

Methyl(R)-2-(6-bromo-1-oxoisoindolin-2-yl)-2-(5-fluoro-2-hydroxyphenyl)acetatewas synthesized by following the reaction scheme described above inExamples 1-4.

Step 3: Synthesis of methyl(R)-2-(6-bromo-1-oxoisoindolin-2-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

To a solution of methyl(R)-2-(6-bromo-1-oxoisoindolin-2-yl)-2-(5-fluoro-2-hydroxyphenyl)acetate(350 mg, 0.89 mmol) in dichloromethane (5 mL) were added methoxymethylchloride (0.17 mL, 2.25 mmol) and DIEA (0.47 mL, 2.70 mmol). Thereaction mixture was warmed to 30° C. and stirred for 4 hr. Theresulting mixture was diluted with dichloromethane and washed with waterand brine. The organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified byflash column chromatography (Hex:EtOAc=80:20 to 20:80) to obtain methyl(R)-2-(6-bromo-1-oxoisoindolin-2-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate(403 mg, 92%).

Step 4: Synthesis of tert-butyl(R)-4-(4-(2-(1-(5-fluoro-2-(methoxymethoxy)phenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenyl)piperazine-1-carboxylate

tert-Butyl(R)-4-(4-(2-(1-(5-fluoro-2-(methoxymethoxy)phenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenyl)piperazine-1-carboxylatewas synthesized by following the reaction scheme described above inExamples 1-4.

Step 5: Synthesis of(R)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindolin-2-yl)-N-(thiazol-2-yl)acetamide

To a solution of tert-butyl(R)-4-(4-(2-(1-(5-fluoro-2-(methoxymethoxy)phenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-3-oxoisoindolin-5-yl)phenyl)piperazine-1-carboxylate(42 mg, 0.061 mmol) in dichloromethane (1.6 mL) was addedtrifluoroacetic acid (0.4 mL). The reaction mixture was stirred for 3hr. The resulting mixture was concentrated and trifluoroacetic acid wasremoved under reduced pressure. The residue was purified by preparativehigh performance liquid chromatography (HPCL) to obtain(R)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindolin-2-yl)-N-(thiazol-2-yl)acetamide(23 mg, 70%) as an off-white solid. Method B: Rt=0.63 min, MS m/z:543.89 [M+1]. ¹H NMR 500 MHz (DMSO-d₆) δ 12.62 (bs, NH), 10.00 (bs, OH),7.90-7.86 (m, 3H), 7.69-7.65 (m, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.49 (d,J=3.4 Hz, 1H), 7.28 (d, J=3.4 Hz, 1H), 7.15-7.09 (m, 3H), 6.94 (dd,J=4.9, 8.9 Hz, 1H), 6.87 (dd, J=3.1, 9.2 Hz, 1H), 6.34 (s, 1H), 4.64 (d,J=17.7 Hz, 1H), 4.02 (d, J=17.7 Hz, 1H), 3.46-3.42 (m, 4H), 3.27-3.23(m, 4H), 2.56 (bs, NH).

Example 6: Synthesis of2-(1-oxoisoindolin-2-yl)-3-(pyridin-3-yl)-N-(thiazol-2-yl)propanamide(I-143)

Step 1: 2-(1-oxoisoindolin-2-yl)-3-(pyridin-3-yl)propanoic Acid

To a solution of 2-Amino-3-(pyridin-3-yl)propanoic acid (83 mg, 0.5mmol) and phthalaldehyde (67 mg, 0.5 mmol) in CHCl3 (3 mL) was addedacetic acid (0.03 mL, 0.5 mmol) and the resulting mixture was heated to80° C. for 8 hrs. The reaction mixture was concentrated under reducedpressure and purified by preparative high performance liquidchromatography (HPLC) to obtain2-(1-oxoisoindolin-2-yl)-3-(pyridin-3-yl)propanoic acid (100 mg, 71%) asa yellow solid. Rt=0.38 min; MS m/z: 283.25 [M+1].

Step 2:2-(1-oxoisoindolin-2-yl)-3-(pyridin-3-yl)-N-(thiazol-2-yl)propanamide(I-143)

To a solution of 2-(1-oxoisoindolin-2-yl)-3-(pyridin-3-yl)propanoic acid(35 mg, 0.12 mmol) in DCM (2 mL) was added 2-aminothiazole (15 mg, 0.15mmol). After stirring for 1 hr at room temperature, the reaction mixturewas diluted with DCM and washed with water. The organic layer was thendried over sodium sulfate, filtered, concentrated under reducedpressure. The crude product was purified by preparative high performanceliquid chromatography (HPLC) to obtain2-(1-oxoisoindolin-2-yl)-3-(pyridin-3-yl)-N-(thiazol-2-yl)propanamide(I-143, 20 mg, 46%) as an white solid. Rt=0.61 min; MS m/z: 365.36[M+1].

Example 7: Biochemical Studies

EGFR Protein Expression and Purification

Constructs spanning residues 696-1022 of the human EGFR (including wildtype and L858R, L858R/T790M, T790M, and T790M/V948R mutant sequences)were prepared in a GST-fusion format using the pTriEX system (Novagen)for expression in Sf9 insect cells essentially as described. (Yun, C. H.et al. The T790M mutation in EGFR kinase causes drug resistance byincreasing the affinity for ATP. Proc Natl Acad Sci USA 105, 2070-2075(2008); Yun, C. H. et al. Structures of lung cancer-derived EGFR mutantsand inhibitor complexes: mechanism of activation and insights intodifferential inhibitor sensitivity. Cancer Cell 11, 217-227 (2007)) EGFRkinase proteins were purified by glutathione-affinity chromatographyfollowed by size-exclusion chromatography after cleavage with TEV orthrombin to remove the GST fusion partner following establishedprocedures. (Yun, C. H. et al. Proc Natl Acad Sci USA 105, 2070-2075(2008); Yun, C. H. et al. Cancer Cell 11, 217-227 (2007)

High-Throughput Screening

Purified EGFR-L858R/T790M enzyme was screened against compounds of thepresent disclosure using HTRF-based biochemical assay format. Thescreening was performed at 1 μM ATP using a single compoundconcentration (12.5 μM). 1322 top hits were picked for follow-up IC₅₀confirmation. IC₅₀ values were determined at both 1 μM and 1 mM ATP toidentify both ATP competitive and non-competitive compounds. Hits werealso counter-screened against wild type EGFR to evaluate the mutantselectivity.

The HTRF-based screen was carried out using 1 μM ATP, and activecompounds were counter-screened at 1 mM ATP and against wild type EGFRto identify those that were potentially non-ATP-competitive and mutantselective. This strategy identified several compounds of distinctchemical classes that were both selective for the L858R/T790M mutantover WT EGFR and relatively insensitive to ATP concentrations,suggesting an allosteric mechanism of action. Among the compoundsidentified in the screen, EGFR allosteric inhibitor-1 (FIG. 1A) was ofparticular interest due to its potency and selectivity for mutant EGFR(IC₅₀=0.033 LM for L858R/T790M at 1 mM ATP, IC₅₀>50 μM for wild typeEGFR). Further characterization of the mutant-selectivity of Compound A1revealed similar activity against L858R/T790M and T790M mutants, withapproximately 2-fold decreased potency against L858R mutant EGFR.

HTRF-Based EGFR Biochemical Assays

EGFR biochemical assays were carried out using a homogeneoustime-resolved fluorescence (HTRF) assay as described previously. Thereaction mixtures contained 1 μM biotin-Lck-peptide substrate, wild typeor mutant EGFR enzyme in reaction buffer (50 mM HEPES pH 7.1, 10 mMMgCl₂, 0.01% BSA, 1 mM TCEP and 0.1 mM Na₃VO₄) at a final volume of 10μL. Enzyme concentrations were adjusted to accommodate varying kinaseactivity and ATP concentrations (0.2-0.4 nM L858R/T790M; or 2-4 nML858R, or 2-4 nM T790M, or 40 nM WT). All reactions were carried out atroom temperature in white ProxiPlate™ 384-well Plus plates (PerkinElmer)and were quenched with 5 μL of 0.2 M EDTA at 60 min. Five μL per well ofthe detection reagent containing 2.5 ng PT66K (Cis-bio) and 0.05 μg SAXL(Prozyme) were added, and the plates were then incubated at roomtemperature for 1 hour and read with an EnVision plate reader. For IC₅₀determinations, compounds of the present disclosure were diluted intoassay mixture (final DMSO 0.5%), and IC₅₀ values were determined by12-point inhibition curves (from 50 to 0.000282 μM) in duplicate underthe assay conditions as described above.

Structure Determination Using Compound A1

Prior to crystallization, 0.1 mM of EGFR-T790M/V943R was incubated for 1hour with 0.5 mM Compound A1, 1 mM Adenosine 5′-(β,γ-imido)triphosphate(AMP-PNP) and 10 mM MgCl₂ at room temperature. Crystals of T790MV943REGFR in complex with Compound A1 were prepared by hanging-drop vapordiffusion method over a reservoir solution containing 0.1M Bis-Tris pH5.5, 25% PEG 3350, 5 mM tris (2-carboxyethyl)-phosphine (TCEP). Crystalswere flash-frozen in liquid nitrogen after rapid immersion in acryoprotectant solution containing 0.1 M Bis-Tris 5.5, 25% PEG3350, 10%ethylene glycol and 5 mM TCEP. Diffraction data were recorded using aMar343 image plate detector on a rotating anode source at 100 K. Datawere processed and merged with HKL2000, as described previously. Thestructure was determined by molecular replacement with the programPHASER using an inactive EGFR kinase structure (PDB 2GS7) as the searchmodel. Repeated rounds of manual refitting and crystallographicrefinement were performed using COOT and REFMAC. The inhibitor wasmodeled into the closely fitting positive Fo-Fc electron density andthen included in following refinement cycles. Topology and parameterfiles for the inhibitors were generated using PRODRG.

To better understand the mechanism of inhibition and mutant-selectivityof the compounds of the present disclosure, the crystal structure ofCompound A1, and known EGFR inhibitors, lapatinib and neratinib, boundto T790M-mutant EGFR, were determined. The structure reveals that thecompound binds in an allosteric pocket that is created in part by theoutward displacement of the C-helix in the inactive conformation of thekinase (FIGS. 1B and 1C). The compound binds as a “three-bladedpropeller” with the aminothiazole moiety inserted between the mutantgatekeeper methionine and active site residue Lys745. The phenylsubstituent extends into a hydrophobic cleft at the back of the pocketand is in contact with Leu777 and Phe856. Finally, the oxaindole groupextends along the C-helix toward the solvent exposed exterior. It packsbetween Ile759 and Met766 in the C-helix, and is also in van der Waalscontact with Leu788. The compound also forms a hydrogen bond with Asp855in the DFG motif. In further support of a non-ATP competitive mechanism,the ATP-analog AMP-PNP is bound in the expected manner in the activesite cleft (FIG. 1C).

EGFR inhibitors lapatinib and neratinib extend into the allosteric siteand make interactions that resemble those of two of the three blades ofthe allosteric agents (FIGS. 3A and 3B). (Wood, E. R. et al. A uniquestructure for epidermal growth factor receptor bound to GW572016(Lapatinib): relationships among protein conformation, inhibitoroff-rate, and receptor activity in tumor cells. Cancer Res 64, 6652-6659(2004); Tsou, H. R. et al. Optimization of6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orallyactive, irreversible inhibitors of human epidermal growth factorreceptor-2 kinase activity. Journal of medicinal chemistry 48, 1107-1131(2005)) These ATP-competitive inhibitors are not mutant selective, andthey span both the ATP and allosteric sites. Notably, the EGFRallosteric pocket is roughly analogous to a site in MEK1 that istargeted by a number of allosteric inhibitors that are now in clinicaltrials. (Zhao, Y. & Adjei, A. A. The clinical development of MEKinhibitors, Nature reviews. Clinical oncology 11, 385-400, doi:10.1038/nrclinonc.2014.83 (2014)) Despite the similar location of theMEK allosteric site, there is not structural correspondence in thebinding modes of the respective allosteric inhibitors (FIGS. 3B and 3C).

The mutant-specificity of the EGFR allosteric inhibitors arises from atleast two effects. Most obviously, the direct contact of theaminothiazole group with the mutant gatekeeper methionine residue canexplain the selectivity for the T790M mutant. Secondly, selectivity forL858R (and by extension the lack of activity on wild type EGFR) islikely attributable to the fact that the compound cannot bind the fullyinactive conformation of the kinase, in which the N-terminal portion ofthe activation loop forms a short helix that includes Leu858. Simplemodeling reveals that Compound A1 binding will be precluded by stericclashes of the oxindole group with Leu858 and Leu861 in this region inthe fully inactive conformation of the wild type receptor. Priorstructural analysis of the L858R mutant revealed that it destabilizesthis inactive conformation to promote kinase activation. (Yun, C. H. etal. Structures of lung cancer-derived EGFR mutants and inhibitorcomplexes: mechanism of activation and insights into differentialinhibitor sensitivity. Cancer Cell 11, 217-227 (2007)) In the presentstructure, Leu858 assumes an alternate position and the remainder of theactivation loop is disordered. Thus, binding of the allosteric inhibitoris favored in the L858R mutant where this constraint is released. Thecompounds may also inhibit other mutants with a similar mechanism ofactivation, such as L861Q. By contrast, it is not expected the compoundsto bind most exon19 deletion variants. Although no structure isavailable for any of the exon19 deletions, these mutations shorten theloop leading into the C-helix and likely lock it in the inward activeposition, thereby precluding binding of the allosteric agents,irrespective of the presence of the T790M mutation.

H1975, H3255 & HaCaT Target Modulation Assays

Tissue Culture

Cells were maintained in 10% FBS/RPMI supplemented with 100 μg/mLPenicillin/Streptomycin (Hyclone #SH30236.01). The cells were harvestedwith 0.25% Trypsin/EDTA (Hyclone #SH30042.1), re-suspended in 5%FBS/RPMI Pen/Strep and plated at 7,500 cells per well in 50 μL of mediain a 384-well black plate with clear bottoms (Greiner #789068G). Thecells were allowed to incubate overnight in a 37° C., 5% CO₂ humidifiedtissue culture incubator. The 12-point serial diluted test compoundswere transferred to the plate containing cells by using a 50 nL Pin Headdevice (Perkin Elmer) and the cells were placed back in the incubatorfor 3 hours.

Phospho-EGFR (Y1173) Target Modulation Assay

HaCaT cells were stimulated with 10 ng/mL EGF (Peprotech # AF-100-15)for 5 minutes at room temperature. Constitutively activated EGFR mutantcell lines (H1975 and H3255) were not stimulated with EGF. The media wasreduced to 20 μL using a Bio-Tek ELx 405 Select™ plate washer. Cellswere lysed with 20 μL of 2× Lysis buffer containing protease andphosphatase inhibitors (2% Triton X-100, 40 mM Tris, pH 7.5, 2 mM EDTA,2 mM EGTA, 300 mM NaCl, 2× complete cocktail inhibitor (Roche #11 697498 001), 2× Phosphatase Inhibitor Cocktail Set II and Set III (Sigma#P5726 and #P0044)). The plates were shaken for 20 minutes. An aliquotof 25 μL from each well was transferred to prepared ELISA plates foranalysis.

For the experiment studying the effect of EGF pre-treatment on compound(e.g., compounds of the present disclosure) target modulation, H1975cells were harvested and plated in 0.5% FBS/RPMI Pen/Strep. On thefollowing day, cells were pre-treated with 0.5% FBS/RPMI media with orwithout 10 ng EGF/mL for 5 minutes. Compound (i.e., compounds of thepresent disclosure) was added and assay was carried out as describedabove.

Phospho-EGFR (Y1173) ELISA

Solid white 384-well high-binding ELISA plates (Greiner #781074) werecoated with 5 μg/mL goat anti-EGFR capture antibody overnight in 50 mMcarbonate/bicarbonate pH 9.5 buffer. Plates were blocked with 1% BSA(Sigma #A7030) in PBS for 1 hour at room temperature, and washes werecarried out with a Bio-Tek ELx405 Select™ using 4 cycles of 100 μL TBS-T(20 mM Tris, 137 mM NaCl, 0.05% Tween-20) per well. A 25 μL aliquot oflysed cell was added to each well of the ELISA plate and incubatedovernight at 4° C. with gentle shaking. A 1:1,000 anti-phospho-EGFR in0.2% BSA/TBS-T was added and incubated for 2 hours at room temperature.After washing, 1:2,000 anti-rabbit-HRP in 0.2% BSA/TBS-T was added andincubated for 1 hour at room temperature. Chemiluminescent detection wascarried out with SuperSignal ELISA Pico substrate. Signal was read onEnVision plate reader using built-in UltraLUM setting.

Western Blotting

Cell lysates were equalized to protein content determined by CoomassiePlus™ Protein Assay Reagent (ThermoScientific #1856210) and loaded onto4-12% NuPAGE Bis-Tris gels with MOPS running buffer with LDS Samplebuffer (supplemented with DTT. Gel proteins were transferred to PVDFmembranes with an iBlot® Gel Transfer Device. 1× Casein-blockedmembranes were probed with primary antibodies overnight at 4° C. on anend-over-end rotisserie. Membranes were washed with TBS-T andHRP-conjugated secondary antibodies were added for 1 hour at roomtemperature. After washing, HRP was detected using Luminata™ ForteWestern HRP Substrate reagent and recorded with a Bio-Rad VersaDocimager.

Proliferation Assay

H1975, H3255 and HaCaT cell lines were plated in solid white 384-wellplates (Greiner) at 500 cells per well in 10% FBS RPMI P/S media. Usinga Pin Tool, 50 nL of serial diluted compounds of the present disclosurewere transferred to the cells. After 3 days, cell viability was measuredby CellTiter-Glo (Promega) according to manufacturer's instructions.Luminescent readout was normalized to 0.1% DMSO-treated cells and emptywells. Data was analyzed by non-linear regression curve-fitting and EC₅₀values were reported. Inhibition data of an EGFR T790M/L858R cell linefor exemplary compounds of the present disclosure combined withcetuximab (% cetuximab, 1.0 μM drug concentration with 1.0 μg/mLcetuximab) can be found in Table 2 below.

Ba/F3 Cell Proliferation Models

The EGFR mutant L858R, Del E746_A750, L858R/T790M, DelE746_A750/T790M,L858R/T790M/C797S and Del/T790M/C797S Ba/F3 cells have been previouslydescribed (Zhou, W., Ercan, D., Chen, L., Yun, C. H., Li, D.,Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R.,et al. “Novel mutant-selective EGFR kinase inhibitors against EGFRT790M,” Nature 462, (2009), 1070-1074). All cell lines were maintainedin RPMI 1640 (Cellgro; Mediatech Inc., Herndon, Calif.) supplementedwith 10% FBS 100 units/mL penicillin, 100 units/mL streptomycin, and 2mM glutamine. L858R cells were maintained in ACL-4 media (Invitrogen,Carlsbad, Calif.) supplemented with 5% FBS, 100 units/mL penicillin, 100units/mL streptomycin, and 2 mM glutamine. The EGFR I941R mutation wasintroduced via site directed mutagenesis using the Quick ChangeSite-Directed Mutagenesis kit (Stratagene; La Jolla, Calif.) accordingto the manufacturer's instructions. All constructs were confirmed by DNAsequencing. The constructs were shuttled into the retroviral vector JP1540 using the BD Creator™ System (BD Biosciences). Ba/F3 cells wereinfected with retrovirus and according to standard protocols, asdescribed previously (Zhou et al, Nature 2009). Stable clones wereobtained by selection in puromycin (2 μg/ml).

Growth and inhibition of growth was assessed by MTS assay and wasperformed according to previously established methods (Zhou et al.,Nature 2009). The MTS assay is a colorimetric method for determining thenumber of viable cells that is based on the bioreduction of MTS by cellsto a formazan product that is soluble in cell culture medium and can bedetected spectrophotometrically. Ba/F3 cells of different EGFR genotypeswere exposed to treatment for 72 hours and the number of cells used perexperiment determined empirically and has been previously established(Zhou et al., Nature 2009). All experimental points were set up in sixwells and all experiments were repeated at least three times. The datawas graphically displayed using GraphPad Prism version 5.0 for Windows,(GraphPad Software; www.graphpad.com). The curves were fitted using anon-linear regression model with a sigmoidal dose response.

Inhibition data of an EGFR T790M/L858R Ba/F3 cell line. A indicates a %inhibition of about 75%; B indicates a % inhibition of between about 50%to about 75%; C indicates a % inhibition of between about 25% to about50%; and D indicates a % inhibition of between about 0% to about 25%.

TABLE 2 Compound Activity (% Number inhibition) I-1 A I-2 A I-3 A I-4 AI-5 A I-6 A I-7 A I-8 A I-9 A I-10 A I-11 A I-12 A I-13 A I-14 A I-15 AI-16 A I-17 A I-18 A I-19 A I-20 A I-21 B I-22 A I-23 A I-24 A I-25 AI-26 A I-27 A I-28 A I-29 A I-30 A I-31 A I-32 A I-33 A I-34 A I-35 AI-36 A I-37 A I-38 A I-39 A I-40 A I-41 A I-42 A I-43 A I-44 A I-45 AI-46 B I-47 B I-48 A I-49 A I-50 A I-51 A I-52 A I-53 A I-54 A I-55 BI-56 B I-57 A I-58 B I-59 C I-60 C I-61 C I-62 B I-63 C I-64 B I-65 DI-66 D I-67 C I-68 D I-69 D I-70 D I-71 C I-72 B I-73 C I-74 B I-75 DI-76 B I-77 B I-78 A I-79 D I-80 C I-81 D I-82 C I-83 D I-84 D I-85 DI-86 B I-87 A I-88 C I-89 B I-90 C I-91 D I-92 C I-93 A I-94 C I-95 BI-96 A I-97 A I-98 C I-99 C I-100 D I-101 B I-102 B I-103 C I-104 CI-105 B I-106 B I-107 B I-108 C I-109 B I-110 A I-111 A I-112 D I-113 CI-114 B I-115 D I-116 A I-117 A I-118 A I-119 D I-120 D I-121 D I-122 DI-123 D I-124 D I-125 D I-126 D I-127 A I-128 A I-129 B I-130 C I-131 AI-132 A I-133 D I-134 A

Considering the allosteric mechanism of action the compounds of thepresent disclosure, the extent to which ligand stimulation would affectpotency of inhibition of the mutant receptor was studied. To this end,inhibition of EGFR phosphorylation in H1975 cells in the presence andabsence of EGF using the quantitative ELISA-based assay was examined. Inboth the presence and absence of exogenous EGF (10 ng/ml),representative compounds of the present disclosure inhibited EGFRphosphorylation with a similar EC₅₀, but strikingly, inhibitionplateaued at 50% in the presence of ligand. This phenomenon suggests twopopulations of receptor, one that remains sensitive to the allostericinhibitor upon ligand stimulation, and another, equal in number, that isrendered insensitive. Ligand-induced dimerization of the EGF receptor isknown to induce an asymmetric interaction of the kinase domains, and isan obvious potential source of two receptor populations withdifferential inhibitor sensitivity. (Zhang, X., Gureasko, J., Shen, K.,Cole, P. A. & Kuriyan, J. “An allosteric mechanism for activation of thekinase domain of epidermal growth factor receptor,” Cell 125, 1137-1149(2006)).

In the EGFR asymmetric dimer, the C-lobe of the “activator” subunitimpinges on the N-lobe of the “receiver” subunit, inducing an activeconformation in the receiver by reorienting the regulatory C-helix toits inward, catalytically functional position. In wild-type EGFR, onlythe receiver subunit is activated. Oncogenic mutations in the EGFRkinase domain induce an active conformation even in the absence ofligand stimulation, thus both subunits of a ligand-bound mutant receptorare expected to be catalytically active. In the receiver subunit but notthe activator, outward displacement of the C-helix is impeded by theasymmetric dimer interaction. Because the mutant receptor favors dimerformation and could promote dimerization even in the absence of ligand,this effect could explain the apparent disconnect in biochemical andcellular potencies of the allosteric inhibitor. (Red Brewer, M. et al.Mechanism for activation of mutated epidermal growth factor receptors inlung cancer. Proc Natl Acad Sci USA 110, E3595-3604,doi:10.1073/pnas.1220050110 (2013); Shan, Y. et al. Oncogenic mutationscounteract intrinsic disorder in the EGFR kinase and promote receptordimerization. Cell 149, 860-870, doi:10.1016/j.cell.2012.02.063 (2012)).To test this notion, an I941R point mutation in the C-lobe of thekinase, which is known to block the asymmetric dimer interaction, wasexploited. (Zhang, X., Gureasko, J., Shen, K., Cole, P. A. & Kuriyan,J., “An allosteric mechanism for activation of the kinase domain ofepidermal growth factor receptor,” Cell 125, 1137-1149 (2006); Cho, J.et al., “Cetuximab response of lung cancer-derived EGF receptor mutantsis associated with asymmetric dimerization,” Cancer Res 73, 6770-6779,doi:10.1158/0008-5472.CAN-13-1145 (2013)). The activity of theL858R/T790M mutant is dimerization-independent, and as expected Ba/F3cells bearing the L858R/T790M/I941R triple mutant EGFR proliferated inthe absence of IL-3. In support of our hypothesis, thedimerization-defective mutant was dramatically more sensitive to theallosteric inhibitor.

One therapeutic antibody, cetuximab, targets the extracellular portionof the EGF receptor, blocking ligand binding and preventing dimerformation. (Goldstein, N. I., Prewett, M., Zuklys, K., Rockwell, P. &Mendelsohn, J., “Biological efficacy of a chimeric antibody to theepidermal growth factor receptor in a human tumor xenograft model,” ClinCancer Res 1, 1311-1318 (1995); Li, S. et al., “Structural basis forinhibition of the epidermal growth factor receptor by cetuximab,” CancerCell 7, 301-311, doi: 10.1016/j.ccr.2005.03.003 (2005)) The antibody isnot effective clinically in EGFR-mutant NSCLC, and in cell-based studiescetuximab alone does not inhibit L858R/T790M or Del/T790M mutant EGFR,because their activity is dimerization independent. (Cho, J. et al.Cancer Res 73, 6770-6779, doi:10.1158/0008-5472.CAN-13-1145 (2013)).

Table 3 shows the inhibition data of an EGFR Parental Ba/F3 cell line,EGFR L858R/T790M Ba/F3 cell line, EGFR L858R/T790M Ba/F3 cell line, EGFRDel/T790M, and Del/T790M Ba/F3 cell line treated with compounds of thepresent disclosure or in combination with Cetuximab. A indicates an IC₅₀of <0.5 μM; B indicates an IC₅₀ between about 0.5 μM to about 1 μM; Cindicates an IC₅₀ between about 1 μM to about 10 μM; and D indicates anIC₅₀>10 μM.

TABLE 3 Compound L858R/ L858R/T790M Del/ Del/T790M Number Parental T790MCetuximab T790M Cetuximab I-65 D D A D D I-66 D C A D C I-68 C C A C CI-69 C C A C C I-70 D D A D D I-75 D D A C C I-79 D D A D D I-81 C C A CC I-112 D C A D D I-113 D D A D D I-115 C C A C C I-119 D D A D D I-120C C A C C I-121 C C A C C I-122 C C A D D I-126 — B A — —Mouse Efficacy Studies

EGFR-TL (T790M/L858R) and EGFR-TD (exon 19 deletion-T790M) mice weregenerated as previously described (Li, D., Shimamura, T., Ji, H., Chen,L., Haringsma, H. J., McNamara, K., Liang, M. C., Perera, S. A.,Zaghlul, S., Borgman, C. L., et al., “Bronchial and peripheral murinelung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272and rapamycin combination therapy,” Cancer Cell 12, (2007), 81-93; Zhouet al., Nature 2009). The EGFR-L858R;T790M;C797S (“TLCS”) mutant mousecohort was established briefly as follows: The full-length HuTLCS cDNAwas generated by site-directed mutagenesis using the Quickchange sitedirected mutagenesis kit (Agilent Technologies) and further verified byDNA sequencing. Sequence-verified targeting vectors wereco-electroporated with an FLPe recombinase plasmid into v6.5 C57BL/6J(female)×129/sv (male) embryonic stem cells (Open Biosystems) asdescribed elsewhere (Beard, C., Hochedlinger, K., Plath, K., Wutz, A.,and Jaenisch, R., “Efficient method to generate single-copy transgenicmice by site-specific integration in embryonic stem cells,” Genesis 44,(2006), 23-28). Resulting hygromycin-resistant embryonic stem cloneswere evaluated for transgene integration via PCR. Then,transgene-positive embryonic stem clones were injected into C57BL/6blastocysts, and the resulting chimeras were mated with BALB/c WT miceto determine germline transmission of the TLCS transgene. Progeny of TL,TD and TLCS mice were genotyped by PCR of tail DNA.

The TL and TD mice were fed a doxycycline diet at 6 weeks of age toinduce EGFR TL or TD expression, respectively. The TLCS mice wereintranasally instilled with Ad-Cre (University of Iowa viral vectorcore) at 6 weeks of age to excise the loxP sites, activating EGFR TLCSexpression.

All care of experimental animals was in accordance with Harvard MedicalSchool/Dana-Farber Cancer Institute (DFCI) institutional animal care anduse committee (IACUC) guidelines. All mice were housed in apathogen-free environment at a DFCI animal facility and handled instrict accordance with Good Animal Practice as defined by the Office ofLaboratory Animal Welfare.

In Vivo Treatment and MRI Tumor Volume Quantification

The TL, TD and TLCS mice were monitored by MRI to quantify lung tumorburden before being assigned to various treatment study cohorts. All thetreatment mice had equal amount initial tumor burden. A compound of thepresent disclosure was dissolved in 10% NMP (10%1-methyl-2-pyrrolidinone: 90% PEG-300), and was dosed at 60 mg/kg dailyby oral gavage. Cetuximab was administrated at 1 mg/mouse every threedays by intraperitoneal in injection. MRI evaluation was repeated every2 weeks during the treatment. The animals were imaged with a rapidacquisition with relaxation enhancement sequence (TR=2000 ms, TEeffect=25 ms) in the coronal and axial planes with a 1-mm slicethickness gating with respiratory rates. The detailed procedure for MRIscanning has been previously described (Li et al., 2007). The tumorburden volumes were quantified using 3-dimensional Slicer software.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

The invention claimed is:
 1. A compound of Formula (I′):

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers,or tautomers thereof, wherein: R₁ is (C₆-C₁₀) aryl, or heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the aryl and heteroaryl are eachoptionally substituted with one or more R₁₁; each R₁₁ is independentlyselected from (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy,halogen, NO₂, OH, CN, C(O)R₁₃, C(O)OR₁₃, C(O)NR₁₃R₁₄, NR₁₃R₁₄, (C₃-C₇)cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, (C₆-C₁₀) aryl, and heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl,and heteroaryl are each optionally substituted with one or more R₁₂;each R₁₂ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, OH, CN,(C₃-C₇) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and1-3 heteroatoms selected from N, O, and S, (C₆-C₁₀) aryl, and heteroarylcomprising one or two 5- to 7-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the aryl and heteroaryl are eachoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄)haloalkoxy, halogen, NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄) alkyl)₂, (C₃-C₇)cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3heteroatoms selected from N, O, and S; each R₁₃ is independentlyselected from H, (C₁-C₄) alkyl, (C₃-C₇) cycloalkyl, and heterocyclylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S, wherein the alkyl, cycloalkyl, and heterocyclyl are eachoptionally substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, halogen, OH, NH₂, NH(C₁-C₄) alkyl,N((C₁-C₄) alkyl)₂, and heterocyclyl comprising a 5- to 7-membered ringand 1-3 heteroatoms selected from N, O, and S; each R₁₄ is independentlyH or (C₁-C₃) alkyl; R₂ is H or (C₁-C₃) alkyl; R₃ is H or (C₁-C₃) alkyl;R₄ is

X₁ is N or CR₆; R₆ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, NH₂, (CH₂)_(q)OH, S(O)_(r)R₂₃,or CN; each R₇ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, NH₂,(CH₂)_(q)OH, S(O)_(r)R₂₃, and CN; R₅ is NR₁₅R₁₆; R_(5′) is H or (C₁-C₄)alkyl; R₁₅ is H or (C₁-C₃) alkyl; R₁₆ is (C₆-C₁₀) aryl, or heteroarylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S, wherein the aryl and heteroaryl are each optionallysubstituted with one or more R₁₈; or R₁₅ and R₁₆ together with thenitrogen atom to which they are attached form a 5- or 6-memberedheterocyclyl optionally comprising 1 or 2 additional heteroatomsselected from N, O, and S and optionally substituted with one or moreoxo groups, wherein the heterocyclyl is fused with a phenyl ring whichis optionally substituted with one or more R₁₉; each R₁₈ isindependently selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(O)O(C₁-C₄) alkyl, NO₂,C(O)NH(C₁-C₄) alkyl, NH₂, NH(C₁-C₄) alkyl, and N((C₁-C₄) alkyl)₂,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from halogen, OH, NH₂, NH(C₁-C₄)alkyl, and N((C₁-C₄) alkyl)₂; each R₁₉ is independently selected fromhalogen, O(CH₂)₁₋₃—OH, (C₃-C₇) cycloalkyl, (C₄-C₇) cycloalkenyl,(C₆-C₁₀) aryl, NH—(C₆-C₁₀) aryl, and heteroaryl comprising one or two 5-to 7-membered ring and 1-4 heteroatoms selected from N, O, and S,wherein the aryl and heteroaryl are each optionally substituted with oneor more R₂₀; or two R₁₉ together with the atoms to which they areattached form a (C₆-C₁₀) aryl optionally substituted with one or moreR₂₀; each R₂₀ is independently selected from (C₁-C₄) alkyl, (C₁-C₄)alkoxy, (C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, C(O)OH,C(O)O(C₁-C₄) alkyl, C(O)NR₂₁R₂₂, O(CH₂)₁₋₃—OH, NH₂, OH, CN,O(CH₂)₀₋₃—(C₆-C₁₀) aryl, and (CH₂)₀₋₃-heterocyclyl which comprises a 5-to 7-membered ring and 1-3 heteroatoms selected from N, O, and S,wherein the heterocyclyl is optionally substituted with one or moresubstituents independently selected from (C₁-C₄) alkyl, (C₁-C₄) alkoxy,(C₁-C₄) haloalkyl, (C₁-C₄) haloalkoxy, halogen, NH₂, NH(C₁-C₄) alkyl,N((C₁-C₄) alkyl)₂, S(O)₂NH₂, (CH₂)_(s)OH, C(O)(CH₂)_(s)OH, andC(O)O(C₁-C₄) alkyl); R₂₁ is H or (C₁-C₃) alkyl; R₂₂ is H or (C₁-C₄)alkyl optionally substituted with one or more substituents independentlyselected from NH₂, NH(C₁-C₄) alkyl, N((C₁-C₄)alkyl)₂, and heterocyclylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S; or R₂₁ and R₂₂ together with the nitrogen atom to which theyare attached form a 5- or 6-membered heterocyclyl optionally containing1-2 additional heteroatoms selected from N, O, and S; R₂₃ is H or NH₂; mand n are each independently 0 or 1; each r and each q are independently0, 1, or 2; each s is 1 or 2; and p is 0, 2, 3 or 4; provided that whenm is 0, n is 0, p is 0, R₁₅ and R₁₆ together with the nitrogen atom towhich they are attached form an unsubstituted isoindolinone, and R₆ isH, then R₁ is not

and provided that R₄ is not 4-fluoro-2-hydroxyphenyl.
 2. The compound ofclaim 1, wherein m is
 0. 3. The compound of claim 1, wherein R₅ is

optionally substituted with one to three R₁₉.
 4. The compound of claim1, wherein one R₁₉ is phenyl or heteroaryl comprising one or two 5- to7-membered ring and 1-4 heteroatoms selected from N, O, and S, whereinthe phenyl and heteroaryl are each optionally substituted with one ormore R₂₀.
 5. The compound of claim 1, wherein R₂₀ is halogen,O(CH₂)₁₋₃—OH, or optionally substituted (CH₂)₀₋₃-heterocyclyl whichcomprises a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S.
 6. The compound of claim 1, wherein R₂₀ is piperazinyl orpiperazinyl substituted with one or more substituents independentlyselected from (C₁-C₄) alkyl, S(O)₂NH₂, (CH₂)_(s)OH, and C(O)(CH₂)_(s)OH.7. The compound of claim 1, wherein R₁ is


8. The compound of claim 1, wherein R₄ is phenyl substituted with two ormore R₇.
 9. The compound of claim 1, wherein at least one R₇ is halogenor at least one R₇ is halogen and at least one R₇ is OH.
 10. Thecompound of claim 1, wherein n is
 0. 11. The compound of claim 1,wherein n is
 1. 12. A compound of the following structure

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers,or tautomers thereof.
 13. A pharmaceutical composition comprising acompound of claim 12, and a pharmaceutically acceptable carrier.
 14. Apharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable carrier.
 15. The compound of claim 1, ofFormula (I):

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers,or tautomers thereof, wherein R₆ is H, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, NH₂, OH, or CN; andeach R₇ is independently selected from (C₁-C₄) alkyl, (C₁-C₄) haloalkyl,(C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, halogen, NO₂, NH₂, OH, and CN. 16.The compound of claim 1, wherein R₅ is


17. The compound of claim 1, wherein R₁ is

substituted with one or more substituents independently selected from(C₁-C₄) haloalkyl, halogen, C(O)R₁₃, C(O)OR₁₃, C(O)NR₁₃R₁₄, andheteroaryl.
 18. The compound of claim 1, wherein R₄ is unsubstitutedphenyl.
 19. The compound of claim 1, wherein p is 0 or
 2. 20. Thecompound of claim 12, of the following structure


21. A compound selected from:

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers,or tautomers thereof.